According to published literature and available data, parasitic infections represent a possible complication after SOT. Studies on this topic are evolving fields that are receiving increased recognition.
When parasitic infections occur in immunosuppressed people, they can manifest with several features. Clinical severity and outcome certainly depend on parasite features, innate and acquired host immunity as well as on immune interaction between parasite and host.
Prolonged fever alone or in combination with other systemic manifestations, anemia, lower gastrointestinal symptoms, and variable stigmata of organ involvement represent the most frequent clinical pattern, occurring in many parasitosis. Actually, it is difficult to identify and interpret all potential clinical patterns in which non-infectious events such as conditioning regimens, drugs, and acute GVHD may interfere.
Means of acquisition, clinical features, diagnostic methods and treatment measures of the most serious parasitic-specific infections reported in SOT recipients are listed below.
5.1. Non-Intestinal Protozoan Infections
is a life-threatening opportunistic infection that may affect transplanted people. It is caused by the coccidian Toxoplasma gondii
. Its occurrence in these patients is closely related to the prevalence of toxoplasmosis in the general population, which is high in Europe, but declining in recent decades [205
In published and available reviewed literature, we found 162 case reports of toxoplasmosis occurring after SOT [4
]. Of interest, in SOT recipients, toxoplasmosis results more frequently from transmission of the parasite with the transplanted organ from a Toxoplasma
-seropositive donor (D+) to a Toxoplasma
-seronegative recipient (R−). This risk is greater for transplantation of organs with high numbers of tissue cysts, e.g., the heart (see muscles sustaining parasite encystment), and it is markedly lower for the other organs [207
]. Transmission of T. gondii
from a D+ to an R+ may also occur. In this case, graft transmission is difficult to confirm and to differentiate from a reactivation of latent infection in the recipient. However, the hypothesis of reinfection of an R+ from a D+ has been suggested by Robert-Gangneux et al. [207
]. In this study, western blot (WB) analysis of post-transplant sera of R+ showed neosynthesized IgG, probably related to the recognition of the new parasite strain acquired via the transplanted organ from a D+. This reinfection could be proved only with the identification of the infecting strain(s), by serotyping or genotyping [208
In case of a recently infected donor, the possible presence of T. gondii in the blood represents a potential risk of transmission to an R−.
According to the literature data on post-transplant toxoplasmosis, transmission occurred through graft in 31.5% (n 51), de novo infection in 9.9% (n 16) and reactivation in 8% (n 13). However, in 50.6% (n 82) the modality of infection remained unknown.
As already said, although heart transplant is riskier for organ-related toxoplasmosis than liver, lung, or kidney transplant, data from the last decade published records showed kidney transplant as the most frequently implicated in post-transplant toxoplasmosis (n 75, 46.3%), followed by heart (n 55, 34%). Liver (n 19, 11.7%), bowel, pancreas, lung and simultaneous multivisceral (few cases) transplants have also been reported.
Toxoplasmosis in the immunocompromised host presents with pyrexia, lymphadenopathy, and multiorgan involvement. Anemia is common, and a hemophagocytic syndrome has been reported in several cases [211
]. Encephalitis, meningoencephalitis, and cerebral mass lesions are serious and frequent complications [9
]. Chorioretinitis, similar to that observed in Cytomegalovirus (CMV) infection, frequently occurs [25
]. Myocarditis and pneumonitis are also reported [7
According to collected data, primary toxoplasmosis acquired through the graft is usually more severe than reactivation disease (mortality of 31.4% for graft-related toxoplasmosis versus 7.7% for reactivation cases) and in the case of graft transmission, it occurs much earlier than reactivation, often within 100 days of transplantation.
The serological status for infection with T. gondii
in both the donor and recipient must be determined prior to transplantation. After transplantation, the diagnostic work ideally includes not only traditional serological assays but also sensitive techniques like comparative WB between pre- and post-transplant pattern [207
] and polymerase chain reaction (PCR) in biological samples [215
]. The study of cellular immune response using toxiferon, useful for the diagnosis of congenital toxoplasmosis [216
], is under evaluation in transplanted individuals in few Centres, but to our knowledge no report is present in the literature about the use of such a method in the follow up of transplanted individuals. Moreover, the definitive diagnosis often requires the direct demonstration of parasites (e.g., histologically) or parasitic DNA in blood, bone marrow, cerebrospinal fluid (CSF), bronchoalveolar lavage (BAL) fluid or biopsy specimens. Due to the immunocompromised status of the patients, the serological tests could become less useful for the diagnosis, because of their reduced sensitivity in these conditions.
There is good evidence that in R− of organs from a D+, prophylaxis with trimethoprim-sulfamethoxazole (TMP-SMZ) immediately after transplant reduces the incidence of primary infection: particularly in heart transplant, the occurrence decreases from more than 50% without prophylaxis [217
] to about 5% with prophylaxis [218
]. However, fatal disseminated toxoplasmosis has been reported even in the case of seropositivity match, suggesting that prophylaxis should be extended also in these cases [13
Seronegative candidates must be re-checked immediately before transplant in order to avoid unnecessary chemoprophylaxis, in case of seroconversion. All R− of organs from a D− should follow behavior and dietetic rules to avoid exogenous infection, and should be tested for T. gondii antibodies every six months. R− of organs from a D+ are treated with TMP-SMZ immediately after transplant; moreover, they should follow hygiene and dietetic rules such as those for recipients of organs from a D−.
In these patients, serological tests should be carried out at the end of chemoprophylaxis and then every six months. All patients, including those seropositive before transplant, should be tested for T. gondii
serology when presenting with suggestive symptoms. Mild presentations and nonspecific symptoms should raise a suspicion of toxoplasmic disease, particularly after antireject treatment [14
]. In cases of strong clinical suspicion, with or without laboratory diagnostic confirmation, full regimen treatment (TMP-SMZ or pyrimethamine-sulphadiazine, as standard treatmet, or clindamycin, clarithromycin, azithromycin or atovaquone, as alternatives) should be recommended [3
Regarding treatment, some limitations exist because of potential drug to drug interaction between anti-Toxoplasma
and immunosuppressive treatments. For example, sulfadiazine or SMX together with cyclosporine (CsA) or tacrolimus (TAC) increases risk of kidney damage, azithromycin together with TAC increases the risk of arrhythmia; sulfadiazine and clindamycin therapy can decrease CsA concentration [3
]. On the other hand, the possibility that CsA possesses anti-Toxoplasma
activity must be considered [3
is a vector-borne tissue parasitic disease, localized (cutaneous and muco-cutaneous) or systemic (visceral leishmaniasis = VL), caused by the kinetoplastidae Leishmania
genus. Cases are recorded among patients undergoing kidney, liver, heart, lung and pancreas transplantation, with the most significant association with kidney transplantation (84.1%, based on the 127 cases reported in the literature) [28
]. VL is the most frequently observed clinical presentation, followed by mucosal and more rarely, cutaneous. Like other parasites, Leishmania
spp. can cause asymptomatic infection and then remain dormant in the host for many years, becoming clinically apparent during periods of immunosuppression [219
]. As a consequence, leishmaniasis must always be considered in the differential diagnosis of febrile immunosuppressed transplant recipients (especially if renal) with fever, pancytopenia with or without allograft dysfunction [219
], especially in endemic areas. The diagnosis in immunosuppressed patients is difficult because of the variability of symptoms and clinical signs, and the poor sensitivity of serology in this setting. Aspiration and biopsy of the bone marrow is the preferred method to confirm infection in such individuals [219
]. For kidney transplantation, renal biopsy is also required in the case of graft dysfunction, allowing differential diagnosis between graft rejection, drug-related nephrotoxic lesions and parasitic parenchyma infiltration. The pre-operative check-up with serological testing for leishmaniasis of both transplant patients and donors and the regular post-transplant serological monitoring (although with limitations due to immunosuppressive status) of recipients should be performed to identify people at higher risk of leishmaniasis. Primary prophylaxis is not routinely used, but infection outcome depends on early diagnosis and effective antiparasitic therapy [55
]. Treatment choice is conditioned by toxicity and drug interactions, which is even more important in these patients [55
]. For this reason, liposomal amphotericin B may be considered the treatment of choice of VL, in consideration of the low incidence of side effects [3
5.2. Chagas’ Disease
Chagras’ disease is another vector-borne parasitic disease, but caused by the American Trypanosoma
, which has a very important impact on public health in Latin America [220
Among the different ways of transmission, that with transplanted organs is reported along with reactivation of dormant infection in transplant recipients. In particular, of 88 SOT recipients described in literature as having trypanosomiasis, 29 (32.9%) had a demonstrated primary infection due to well established transmission through allograft; 49 (55.7%) had a reactivation, 2 (2.3%) had de novo infection, and 8 (9.1%) did not have a determined mechanism [15
The most significant association is reported with heart transplantation (60.2%, based on the 53 cases reported in the literature), with kidney transplantation second (22.7%, based on the 20 cases reported in the literature).
Indeed, Trypanosoma cruzi
itself is responsible for a significant proportion of end-stage cardiomyopathy and heart transplant for Chagas’ heart disease should be regarded as a valuable treatment option [221
]. Reactivation in Chagasic heart transplant recipients has been reported to occur in between 26.5% [66
] and 42.9% [221
] of patients with great variability among transplant Centers.
In reported data in this review, Trypanosoma cruzi disease after heart transplantation occurred for reactivation in more than 80% (n 43/53) of cases.
Early diagnosis is needed [73
], because of the high rate of morbidity and possible mortality, which are not however more relevant than in non-infected transplanted subjects. Indeed, survival probability for Chagasic heart transplant recipients at 1 month, 1 year, 4 year, and 10 year follow-ups are 83%, 71%, 57%, and 46%, respectively [65
], better than that seen in non Chagas’ heart transplant recipients [221
Like the native disease, acute, chronic, and reactivated trypanosomiasis in transplant recipients manifests with variable pattern from asymptomatic forms to life-threatening problems. Fever, myalgia, lymphadenopathy, hepatosplenomegaly and subcutaneous nodules are the most prevalent manifestations; less commonly meningoencephalitis and myocarditis can occur during the acute phase, while potentially lethal cardiomyopathy, megasyndrome (megaesophagus/megacolon), or both, can occur during the chronic phase. Complete heart block is a possibility, presenting clinical feature in patients with reactivation.
Diagnosis involves detection of circulating parasites by microscopic examination and blood culture in the acute phase, and by serology thereafter [73
]. For heart transplantation, endomyocardial biopsy allows differentiation between graft rejection and parasitic disease. The pre-operative check-up with serological testing for T. cruzi
of both transplant patients and donors is standard practice: [73
] even asymptomatic persons testing positive are probably infectious for life, with low levels of parasite in blood and other tissues [73
]. In case of mismatch donor/recipient, follow-up schedule and pre-emptive therapy must be performed to abate the parasitaemia and avoid clinical illness [65
Benznidazole is the treatment of choice [3
]. Nifurtimox is an effective alternative [3
life cycle with a hepatic and an erythrocyte stage, allows the transmission of infection either with SOT or with blood transfusion, respectively. In such a setting, malaria remains a rare complication. However, post-transplantation malaria, although uncommon, must be considered particularly when either the recipient or the donor comes from a region endemic to malaria [90
Primary infection or reinfection is a distinct risk in exposed transplant recipients. In published and available literature, post-transplant malaria reported cases involve kidney (16 cases, 59.3%), liver (5 cases, 18.5%), and heart (2 cases, 7.4%) [83
]. Among these patients, 13 had a primary infection due to well clarified transmission through allograft (n 11, 40.7%) or blood/blood products (n 1, 3.7%), and 1 patient (3.7%) had a documented de novo infection. Nevertheless, in most of them the mechanisms of transmission were not clearly determined (n 14, 51.8%).
The clinical picture of malaria in transplant recipients is usually severe, owing to the impaired immune response. It is characterized by pyrexia, which may lack the typical periodicity or rigors. Anemia is severe, being typically hemolytic and occasionally hemophagocytic. It is often associated with thrombocytopenia [86
]. Hepatosplenic γδ-cell lymphoma probably attributed to malarial infection, has been described in kidney transplant recipients [223
]. Acute graft dysfunction may occur as a result of the hemodynamic consequences of P. falciparum
]. Whether the immune response to malarial infection has an impact on subsequent rejection is unknown. Diagnosis is confirmed by examination of a Giemsa- or acridine orange-stained peripheral blood smear. When parasitaemia is low, serological techniques using synthetic peptides as antigen [225
] or DNA probes [226
] are useful for diagnosis.
Antimalarial drugs can be used safely in most patients without incurring problems. However, certain drug-drug interactions must be taken into consideration such as those between quinine and chloroquine with CsA: quinine decreases CsA blood levels, chloroquine increases CsA blood levels [3
]. This may be extrapolated to other immunosuppressive agents which depend on cytochrome P450 for their catabolism. Moreover, TAC together with chloroquine, artemisin combinations, or mefloquine increases the risk of arrhythmia [3
Providing routine malaria prophylaxis probably is not necessary for SOT recipients on maintenance immunosuppressives [227
In addition, a certain protective anti-malarial activity can be postulated from in vitro results obtained with immunosuppressive drugs, such as sirolimus and CsA. Instead, for the moment no conclusive data are available for everolimus and mycophenolic acid if tested at standard doses for the clinical use [3
Beyond any possibility of tailored treatment (specific anti-malarial and selected immunosuppressive combined treatment), prevention and early individuation of at risk patients remains the most important measure.
In this context, careful anamnesis on epidemiological risk has to be seriously considered for each donor and recipient in both malaria endemic and non-endemic zones, considering that infection can still be acquired in non-endemic locations including European or American airports or autochthonous malarial foci [229
is a rare febrile disease, closely related to P. falciparum
malaria, caused by piroplasmia Babesia
, transmitted usually by tick bites. Babesiosis, attributed to graft or transfusion with contaminated blood, has been reported in four SOT recipients, three renal [94
] and one cardiac [95
]. In a further renal recipient affected by babesiosis, the mechanism of transmission has not been well clarified [93
]. Fever, hemolytic anemia, and impaired graft function dominate the clinical picture in the kidney transplanted patient who acquired babesiosis through blood transfusion [94
]; fever, fatigue and abdominal pain have been found in the two kidney transplanted patients acquiring parasitosis through the graft [96
]; acute respiratory distress in the heart transplanted patient [95
]; hemophagocytic syndrome has been reported in the latter, an asplenic renal transplant recipient [93
]. Treatment consists of a combination of clindamycin and quinine, with therapeutic apheresis in severe cases [3
Acanthamoebiasis is a protozoal disease caused by free-living amoebae.
typically complicates corneal transplantation leading to progressive keratitis, corneal opacities, or perforation [97
]. It has also been reported in kidney [98
], liver [105
], lung [101
], and multivisceral transplantation [100
]. The total number of reported cases of post-SOT Acanthamoeba
spp. infection amount to 17 cases. Disseminated acanthamoebiasis in transplant recipients is associated with gastroenteritis, sclerosing cholangitis, encephalitis [100
], and osteomyelitis [99
]. A fatal outcome has been reported in most disseminated cases.
Free-living ameba Balamutia mandrillaris
has been reported as a cause of granulomatous amebic encephalitis. Infection with transplant-transmitted B. mandrillaris amebae
was first identified by CDC reporting two clusters of infections in 2009 [103
] and 2010 [104
is known to spread hematogenously from extra-central nervous system (CNS) sites to the CNS [225
]. Moreover, the described clusters of transplant transmission confirm that hematogenous spread of Balamuthia
occurs from the CNS to other organs as well [231
potentially leads to post-transplantation broncopneumonia. Initial symptoms can be relatively obscure. Thus, possible L. blattarum
infection needs to be screened in patients with respiratory symptoms, especially in those who respond poorly to anti-infection treatment [102
Intestinal protozoan parasitosis
seems to be more common among transplant recipients compared to non-transplanted control subjects [134
]: even parasites that are largely asymptomatic before transplantation may become clinically evident under immunosuppressive treatment.
Gastrointestinal disturbances, particularly diarrhea, both acute and chronic, are frequently observed complications in the first months following transplantation, potentially leading to a deterioration of the general health status in transplanted people. It is difficult to determine the exact etiology of the diarrhea in these patients, including drug-specific effects (i.e., mycophenolate mofetil, antibiotics, colchicines, laxative drug), metabolic conditions, mechanical complications of surgery, acute GVHD, as well as infectious agents (bacteria, such as Clostridium difficile
, Campylobacter jejuni
, Shigella sonnei
and Salmonella enteritidis
and virus, first of all CMV, but also Rotavirus, and parasites, in particular protozoan agents such as Cryptosporidium
spp., Giardia duodenalis
, Entamoeba histolytica
, Entamoeba coli
, Endolimax nana
, Iodamoeba butschili
, Chilomastix mesnili
, and Microsporidia
In this scenario, the screening of samples for intestinal parasitic infections using direct smear, formalin-ether sedimentation, Sheather’s flotation and modified Ziehl-Neelsen staining methods acquires extreme importance [232
Colonoscopy with biopsy should be performed only after the implementation of available noninvasive testing for infectious diarrhea and upon evaluation of all medications taken, to assess the possible cause of diarrhea [114
Intestinal protozoa can be difficult to eradicate even with specific treatment. Reduction in immunosuppressive regimen may hasten clearance of these durable pathogens [3
Beyond localized syndrome, peri-transplant acquired or reactivated enteric protozoan parasitosis can also manifest as extra-intestinal (e.g., hepatobiliary) and systemic diseases because of their aggravation and/or dissemination [232
Helminthic intestinal infections should be actively evaluated in solid organ transplant recipients in both pre- and post-transplant phase.
On the basis of published data, the most frequently intercurrent helminthic intestinal infection in SOT recipients seems to be strongyloidiasis [15
], being occasionally reported infections by other intestinal helminths such as Trichuris trichiura
], Ascaris lumbricoides
] and Dipylidium caninum
As strongyloidiasis is a devastating complication of immunosuppression, SOT recipients can experience serious disease up to death from infection due to such a parasite.
Transplant recipients are at highest risk during the first three months post-transplant. Many organ systems may be affected, particularly in the case of autoinfection evolving in disseminated infection often complicated by polymicrobial sepsis due to enteric organisms adhering to the parasite.
Mortality is placed over 30% [15
], thus careful evaluation of patients at any risk of exposure is essential. Stool specimens as well sputum, urine, and duodenal aspirates may be examined for characteristic organisms. It has been suggested that stool examination become part of the pre-transplantation work-up in all patients, with a more extensive evaluation in patients with a history of travel to, or residence in, an area of endemic infection.
Dormant infection for over 10–20 years must also be considered. Prolonged corticosteroid use, either in the early post-transplant period or during treatment of rejection episodes, may reactivate dormant strongyloidiasis and promote its diffusion in infected hosts.
Regarding the treatment, ivermectin has been increasingly used, being effective, and even more so, tolerated, it represents the first line treatment [3
]. Repeat courses may be needed to eradicate infection [3
]. Albendazole represents the alternative treatment [3
]. The use of CsA in prophylactic immunosuppression seems to reduce strongyloidiaisis occurrence thanks to a strong parasiticidal effect of the drug, which has been documented in mice and humans [3
]. Conversely, tacrolimus seems to increase the risk of infection [3
]. Consequently, treatment decisions should be made on a case-by-case basis.
larva is the most common parasite affecting the CNS. It is unusual in transplant recipients, but the risk must be taken into account: neurocysticercosis (NCC) must be included in the differential diagnosis of patients with CNS involvement and intracranial space-occupying lesions (SOLs) along with tuberculosis (TB), toxoplasmosis, nocardiosis, fungal infections, and post-transplant lymphoproliferative disorder (PTLD) [23
]. The temporal association of the infection with the time elapsed since transplantation, risk factors, clinical manifestations, and neuroimaging characteristics of the lesion can allow a reasoned and rational approach towards the recognition, diagnosis, and appropriate management [195