Parasitic Infections in Solid Organ Transplant Recipients

Abstract

In spite of the high prevalence of human parasitic diseases that affect billions of people throughout the world, only 5% of over 340 known parasitic infections have been reported in transplant recipients (1). Although the number of published papers has increased in recent years, reflecting an increased number of cases, parasitic infections remain the most understudied of all infections related to organ transplantation with only very few prospective trials and no randomized studies that can be accounted for in this field. Recommendations are based primarily on expert opinion (Grade III) unless otherwise stated. Common Features of Parasitic Infection in the Transplant Recipient Parasitic diseases may affect transplant recipients as a result of Recrudescence of latent infections in the previously infected recipient. ‘De novo’ infection by means of Natural infection. Transmission by transplanted organ (or blood product, either before or after transplantation) into a naïve recipient. For the most part, only those organisms that can complete their life cycle within the human host result in more severe infections in an immunocompromised host. Co-infection is a common feature of parasitic infection in transplantation, and invasive disease may be associated with viral infection (particularly cytomegalovirus) or with disseminated bacterial infection. The incidence of parasitic infection is expected to grow in solid organ transplant recipients due to multiple factors: Many geographic areas where parasitic infections are highly prevalent have now active organ transplant programs. Donors and recipients from endemic areas, with latent or asymptomatic infections, are sometimes referred to transplant centers in Western countries. Some patients from developed countries undergo transplantation in highly endemic areas (transplant tourism) and return home with either donor derived or naturally acquired infection(s). Immigrants to Western countries, unaware of their infectious status, are accepted for organ donation without further evaluation for diseases that are prevalent in their countries of origin. With the recent increase in leisure tourism, transplant recipients travel to endemic areas and enhance their risk of exposure. The decrease in cyclosporine-based immunosuppressive regimens and the increased use of newer drugs that lack the anti-parasitic effects of cyclosporine metabolites may result in higher rates of parasitic infection. Epidemiology and risk factors: Toxoplasma gondii infection in transplant recipients can be caused by primary infection transmitted by an allograft or by reactivation of latent infection. Symptomatic toxoplasmosis has been well described after solid organ transplantation; cardiac transplant recipients who are seronegative for toxoplasmosis and receive an organ from a seropositive donor have a 50–75% risk of symptomatic infection without prophylaxis, usually within 3 months after transplantation. Latent infection in the myocardium during cardiac transplantation is the most common method of donor transmission, although it has been transmitted through transplantation of other organs. Infection is worldwide but more common in patients from endemic regions, including France and the moist tropical areas of Latin-America and sub-Saharan Africa, when the prevalence may approach 90%. In the United States, 10–40% of people are seropositive for T. gondii (2, 3). Toxoplamosis is a zoonotic illness; risk factors for primary infection include ingestion of cysts in under cooked meat or contaminated soil, contact with oocysts in feline feces, maternal-fetal transmission or via blood or solid organ transplantation (4). Water-borne transmission of T. gondii has been considered uncommon; a large human outbreak linked to contamination of a municipal water reservoir in Canada by wild felids and the widespread infection by marine mammals in the United States suggest this may be another method of transmission (5). In a recent review of 52 noncardiac SOT-related cases of toxoplasmosis, 86% of patients developed disease within 90 days of transplantation; of these patients, 42% had primary infection, 21% had reactivation or reinfection and 37% had mechanisms that could not be determined (6). Pretransplant screening for prior toxoplasmosis exposure is generally done before heart transplant, and is less frequently done before other organ transplants. To determine whether donors and recipients for all solid organ transplants should have toxoplasmosis serology, a retrospective cohort study of 1,006 solid organ transplant recipients at a single center was performed to examine the incidence of Toxoplasma seroconversion, reactivation, and clinical toxoplasmosis and to evaluate the impact of trimethoprim-sulfamethoxazole (TMP/SMX) prophylaxis (7). Pretransplant Toxoplasma seroprevalence was 13% in donors and 18% in recipients, and the incidence of Toxoplasma donor–recipient mismatch was 10% during the 14-year study period, of whom only 39% of mismatched recipients received TMP/SMX prophylaxis. Only four patients seroconverted, of whom two had received prophylaxis, and there were no cases of clinical disease. This data suggests that in transplant centers with low Toxoplasma seroprevalence, routine screening in solid organ donors and recipients might not be necessary, particularly in the era of routine TMP/SMX prophylaxis. In areas of high seroprevalance, routine screening may be indicated. Diagnosis: Transplant patients with active toxoplasmosis may present with brain abscess, chorioretinitis, pneumonitis or disseminated disease. Definitive diagnosis requires the identification of tachyzoites in biopsy samples or clear seroconversion. Transplant recipients may have a muted serologic response, thus negative serologic results should be viewed cautiously. The presence of multiple ring-enhancing lesions in the basal ganglia or cerebrum on neuro-imaging, especially in the presence of anti-Toxoplasma IgG antibodies, is suggestive of CNS toxoplasmosis and is sufficient to start presumptive treatment for CNS toxoplasmosis. Stem cell transplant recipients often show a variable enhancement pattern, with the lesion enhancement inversely correlated with the severity of immunosuppression; the radiographic appearance in SOT recipients has not been well described (8). Brain biopsy should be considered in nonresponding patients, as the radiographic differences with other infections or malignancies are not sufficiently specific nor sensitive. Cerebrospinal fluid (CSF) may have mild mononuclear pleocytosis and elevated protein hyperproteinorrachia. Identification of anti-T. gondii antibodies by enzyme-linked immunosorbent assay (ELISA) in the CSF is a sensitive and specific method. Toxoplasma can be detected in CSF by DNA amplification in most AIDS patients with CNS infection; tachyzoites can sometimes be seen on centrifuged CSF samples after Giemsa staining. Myocarditis may present with heart failure; the diagnosis is made by seeing tachyzoites on myocardial biopsy. Chorioretinitis (a posterior uveitis) usually present with eye pain and decreased visual acuity, and appears as raised yellow-white, cottony lesions in a nonvascular distribution (unlike the perivascular exudates of CMV retinitis). Vitreal inflammation may be present and a significant percent may have concurrent CNS lesions. Pulmonary disease often presents with fever, dyspnea and nonproductive cough, with radiographic reticulonodular infiltrates and an overall clinical picture that may be indistinguishable from Pneumocystis jiroveci pneumonia; Toxoplasma tachyzoites can be identified in bronchoalveolar lavage (BAL) fluid. Although rare, cutaneous toxoplasmosis has been seen after hematopoietic stem cell transplantation; it may be difficult to diagnose because of the morphologic similarity of T. gondii to other organisms, such as Leishmania and Histoplasma species. Treatment: Optimal treatment after solid organ transplantation has not been well-studied. In general, the literature in AIDS is much more robust. The drugs routinely employed in the treatment of toxoplasmosis treat the proliferative form (tachyzoites) found during the acute phase of infection but do not eradicate the encysted form (bradyzoites) of the parasite. Treatment for active toxoplasmosis generally includes a prolonged course (4–6 weeks or longer) of pyrimethamine and sulfadiazine with folinic acid (to prevent hematologic toxicity from pyrimethamine), followed by suppressive therapy with TMP-SMX. In sulfa allergic recipients, pyrimethamine and folinic acid can be used with high doses of one of the following: clindamycin, clarithromycin or azithromycin, or atovaquone (Table 1), followed by secondary prophylaxis with one of the agents listed further (9). Prevention/Prophylaxis: The routine use of TMP/SMX for post-SOT prophylaxis has decreased the risk of toxoplasmosis (10, 11) and is currently the most common prophylaxis against toxoplasmosis. Pyrimethamine with sulfadiazine is effective and has been used for high-risk cardiac recipients; this combination does not seem to be essential based on clinical data and experience. Numerous studies suggest that primary prophylaxis with TMP/SMX is sufficient, although the optimal dose of TMP/SMX remains unclear. Baren et al reviewed the collective 28-year experience at two urban transplant programs with 596 heart transplant recipients, and found no cases of toxoplasmosis, but all patients received trimethoprim-sulfamethoxazole to prevent Pneumocystis pneumonia; they concluded that additional specific anti-toxoplasmosis prophylaxis is unnecessary in heart transplant recipients (12). Baden et al. reviewed 417 heart transplant recipients on 160 mg of TMP/800 mg of SMX three times a week and found one case (0.2%) of toxoplasmosis in the setting of D+R– while undergoing treatment of acute rejection (10). Muñoz et al. reviewed 315 heart transplant recipients on 160 mg of TMP/800 mg of SMX three times a week, 10% of whom were D+R– and approximately half of whom were given 6 weeks of pyrimethamine, and found no toxoplasmosis in an endemic region (11). Keough et al. reviewed 126 heart transplant recipients on TMP/SMX and found that no toxoplasmosis occurred during prophylaxis, but did occur after prophylaxis was stopped (13). First line prophylaxis should be TMP–SMX dosed at either a double strength tablet (160 mg of TMP/800 mg of SMX) three times a week or a single strength tablet (80 mg of TMP/400 mg of SMX) a day (Grade II-2). More studies have been done with the three times a week dose, although daily dosing may be sufficient. If D+/R– mismatch is present, a double strength tablet (160 mg of TMP/800 mg of SMX) may be given daily, although previously mentioned data suggest that the preceding doses are adequate. TMP–SMX should be dosed based on renal function. Second line prophylaxis should include either atovaquone or dapsone with pyrimethamine and folinic acid; the choice should be made based on tolerance of regimen, cost and availability. Atovaquone may be costly and unpalatable to some recipients, while dapsone can cause anemia in those with G6PD deficiency and pyrimethamine can cause hematologic toxicity. The optimal duration of prophylaxis is not clear; infection has been seen after cessation of prophylaxis. To avoid primary infection, transplant recipients should avoid contact with undercooked meat, soil, water or animal feces that might contain toxoplasmosis cysts. All pre-heart transplant recipients and donors should be serotested for Toxoplasma (Grade II). It is not clear that other organ transplant recipients and donors need to be tested (7). After heart transplant, prophylaxis should be given, as outlined earlier. Disease has been seen after cessation of prophylaxis, the optimal duration of prophylaxis has not been determined, and it is given for life at many transplant centers (Grade III). Acute toxoplasmosis can have protean manifestations and should be included in the differential diagnosis of infectious syndromes after organ transplant. Treatment of acute toxoplasmosis is not well-studied in solid organ transplant recipients; much of our knowledge comes from the treatment of HIV+ patients. Epidemiology and risk factors: This zoonotic disease is caused by a flagellate protozoan parasite, Trypanosoma cruzi. It is transmitted to humans in up to 80% of cases by the contaminated feces of a triatomine insect vector that serves as the parasite intermediate host (14). The disease has been transmitted to humans also by unscreened blood transfusion (5–20%), from infected mother to fetus (0.5–8%) (14), by laboratory accidents, by organ transplantation and rarely by the oral route. It is endemic in most Latin-American countries where it affects 16–18 million people and about 100 million are believed to be at risk (15). Due to recent immigration it is estimated that more than 100,000 infected people are living in United States of America (16). Human disease has two distinct phases: the acute phase and the chronic infection. The acute disease usually resolves spontaneously even if untreated; but without specific treatment the infection persists in spite of strong evidence of immunity and patients become chronically infected with the parasite (14). The indeterminate phase (clinical latency) can last 10–30 years or lifelong. In approximately 30% of patients the chronic phase will evolve into irreversible disease of the heart (27%), the esophagus and the colon (6%) and the peripheral nervous system (3%) (15). Transplant recipients with chronic T. cruzi infection are at risk of reactivation. Heart transplant recipients differ from other solid organ transplant patients and will be considered separately. Chagas disease can also be transmitted from infected donors to naive recipients. Heart transplantation: Chagasic cardiomyopathy is the third leading cause for heart transplantation in Brazil (21.9% of all heart transplants) (17). Posttransplant outcome does not differ significantly from heart transplant for other causes (17, 18). Reactivation after transplantation has been reported to occur in 26.5% (17) to 42.9% (19) of recipients and has been linked by some authors, in multivariate analysis, to rejection treatment, to MMF use and the development of neoplasms (17). Others have not found the same associations (19). Reactivation can occur early after transplant; relapses after treatment have also been described. Clinical manifestations range from asymptomatic parasitemia, fevers, sub-cutaneous involvement to more frequently myocarditis that needs to be differentiated from rejection. Skin manifestations include a rash that may look more like a panniculitis rather than a macular drug rash or may appear to look like erythema nodosum; a skin biopsy may be positive for trypanosomes. Early diagnosis, careful monitoring and good response to treatment allow for an adequate survival (19). Prophylactic treatment early after transplantation was of no benefit in a small cohort of patients and did not prevent reactivation (17). Noncardiac solid organ transplantation: Most of the experience outside of heart transplantation is related to kidney transplantation (20). Reports are very few for other organ transplants. Reactivation has been described mainly within the first posttransplant year. It can reach an incidence of 15–35% with a good response to treatment and good graft and patient survival in long-term follow-up. The most frequent reactivation feature is asymptomatic parasitemia, followed by panniculitis or other manifestations of sub-cutaneous involvement; myocarditis and encephalitis have also been reported. Donors with T. cruzi infection: Two reports of transmission of acute Chagas infection by organ transplantation from unscreened deceased donors have been published in the United States (21, 22). In countries where the disease is endemic, with informed consent, the transplant teams would accept organs from infected donors provided no better donor is available in a reasonable time span, or the patient has been on the waiting list for a long period of time and is deteriorating rapidly. Transmission by infected donors to negative recipients was reported in 1993 in kidney transplant recipients who were prospectively evaluated (23, 24). Transmission from positive donors was detected by systematic search for parasitemia in 19% of seronegative recipients in the first 6 months after transplantation and were cured with trypanocidal treatment (20). No new cases were diagnosed on long-term follow-up. Diagnosis: Diagnosis is achieved by direct parasitological tests, including the examination of whole blood preparations and a concentration method (Strout test) in the acute phase, and with serology tests in the intermediate and chronic stages. The most commonly used are: enzyme immuno-assay (EIA), indirect hemagglutination (IHA) and indirect immunofluorescence (IFA); complement fixation test (CF: Machado Guerreiro test), has been replaced by the former in recent years. All have good sensitivity but less than optimal specificity, and show considerable variation in reproducibility and reliability of results (25). In recent years a new ELISA Test System (Ortho-Clinical Diagnostic) has been licensed by the FDA. It shows a reproducible sensitivity and specificity and no enhanced diagnostic power has been achieved when using simultaneously ‘confirmatory’ tests such as IFA or radioimmuno-precipitation assay (RIPA) (26). Nevertheless, at the time of writing this text the World Health Organization still recommends that at least two different methods of testing must be positive for a diagnosis of T. cruzi infection. Polymerase chain reaction (PCR) based assays, which are now in the final evaluation phase for standardization, have recently been used in clinical research, raising new diagnostic and prognostic possibilities and might provide a useful tool for rapid diagnosis. In chagasic transplant recipients, serology has no utility in diagnosis of reactivation. Direct parasitological tests should be used when searching for reactivation. Also, all available tissue specimens should be evaluated for the presence of amastigotes. PCR-based tests may prove to be beneficial and allow for earlier diagnosis. Treatment: Two drugs are available for treatment: nifurtimox and benznidazole (16). When either is administered for 30–60 days, parasitic cure is achieved in 60–100% of acute cases. Also, evidence supports that trypanocidal treatment modifies the outcome of indeterminate and chronic infection in 20–60% of immunocompetent patients (27). Similar data do not exist for immunocompromised patients. The adverse side effects of these drugs are significant and include dermatitis, peripheral polyneuropathy, weight loss, gastrointestinal disease, hematologic disorders and an increased incidence of lymphoma. Nifurtimox is no longer available in most Latin-American countries, and it is only available through Bayer in Germany and through the Centers for Disease Control and Prevention (CDC) in the United States. Benznidazole is available in Latin-America but not in the United States except from the CDC, nor in Europe. Patients with chagasic myocardiopathy are eligible for heart transplant. Patients with chagasic infection (indeterminate phase) and those with early chronic disease (grade 0–1 Kushnir myocardiopathy) are eligible to receive solid organ transplants. Patients with Chagas disease and grade ≥ 2 Kushnir myocardiopathy should be excluded for nonheart solid organ transplant. All transplant candidates who have lived or traveled extensively in endemic regions, or who were born to mothers from endemic regions or who have received unscreened blood or blood product transfusions should be sero-tested for T. cruzi infection. Caution is needed in the interpretation of negative results in patients with high epidemiological risk that have been treated with immunosuppressive drugs. Active parasitemia should be evaluated in all infected candidates. Evaluation for other latent endemic pathogens should be considered. Pretransplant treatment: There is no prospective randomized evidence to support that pretransplant trypanocidal treatment is useful to inhibit or to avoid posttransplant reactivation. Hence, no recommendation based on evidence can be made at this time. The risk of toxicity from trypanocidal drugs, especially in patients with end stage renal disease and liver insufficiency, largely outweighs its potential benefits (28). Hence, trypanocidal treatment should generally be reserved only for those transplant candidates with proven T. cruzi parasitemia at the time of evaluation. A diagnosis of reactivation should always be considered with unexplained febrile illness, skin involvement, myocarditis or encephalitis. Patients should be systematically monitored for asymptomatic parasitemia (i.e. asymptomatic reactivation) for the first posttransplant year and every time immunosuppression regimen is intensified (i.e. after anti-rejection treatment) to allow for early treatment. A possible schedule would include: once every 1–2 weeks for the first 100 days and monthly thereafter. Biopsies should be performed on all skin/subcutaneous lesions and evaluated for amastigotes. All endomyocardial biopsies, protocol or otherwise, should be evaluated for amastigotes. Reactivation should be treated for 30–60 days with nifurtimox or benznidazole. Serotesting of donors should be performed routinely in regions that have indigenous disease. Serotesting of donors should be carefully considered in those areas that have a significant immigrant population. Infected donors are unacceptable for heart transplantation. The allocation of other organs from infected donors, with appropriate informed consent, could be acceptable for infected recipients; uninfected kidney recipients; possible use in uninfected lung and liver recipients in emergency situations; these patients need to be monitored for disease transmission and promptly treated if transmission occurs. Epidemiology and risk factors: Leishmaniasis is caused by a heterogeneous group of protozoan parasites, belonging to the genus Leishmania and causes a variety of different clinical syndromes. It is estimated that 350 million people are at risk of acquiring the infection and that 12 million may be infected (29). Leishmaniasis is found in tropical and subtropical climates and is endemic in the Mediterranean countries in Europe. More than 90% of the world's cases of visceral leishmaniasis occur in India, Bangladesh, Nepal, Sudan and Brazil (30). The disease may appear as late as 30 years after the initial infection, Therefore, even distant exposure needs to be considered for differential diagnosis. Leishmaniasis can be classified geographically into New World and Old World disease; clinical syndromes can be divided into visceral, cutaneous, or muco-cutaneous leishmaniasis and finally, separation into subgenus, complexes and species can be based upon taxonomy (29, 31). The infection is acquired through the bite of an infected female sandfly. Each species of Leishmania tends to be associated with a single sandfly vector, a major animal reservoir and a major clinical syndrome. Nonetheless, considerable overlap exists (29). In visceral leishmaniasis, liver, spleen and lymph node enlargement are a consequence of the infection of a large number of monocytes in these organs as also bone marrow failure (31). Cutaneous leishmaniasis is the result of parasitization of macrophages in the skin, followed by a necrotizing granulomatous response with lesions healing spontaneously after a variable period of time (usually months) (32). A small subset of patients infected with L. (V.) braziliensis or, very rarely, by other Leishmania species, may develop mucosal disease after months or years. The final outcome of Leishmania infection is the result of the balance between different immune responses. Cell mediated immune mechanisms are ultimately responsible for controlling the infection. Patients with progressive visceral leishmaniasis usually lack a Leishmania-specific immune response (33) in spite of high levels of nonprotective antileishmanial antibodies; patients who resolve the infection have been able to mount a Th1-type response. Derangement of cellular immune mechanisms is a risk factor for the occurrence of symptomatic and severe infections and for increased mortality (31). Infections caused by Leishmania species have been increasingly reported in transplant recipients since the first case was described in 1979 (34). The clinical picture may simulate other infections, and only a high index of suspicion will lead to the diagnosis. Cutaneous and mucocutaneous presentations are rare and have a protracted time interval between transplantation and disease manifestations (34). Some have occurred in geographical areas where mucosal disease-producing Leishmania species are quite infrequent (35-37). Visceral leishmaniasis has been described predominantly in kidney transplant recipients (38-65) but has also been seen in kidney–pancreas (66), liver (55, 67), lung (68) and heart (55, 69) transplant recipients. Visceral leishmaniasis should always be considered in the differential diagnosis of patients with fever who live, have lived in and who have traveled extensively to endemic areas, even in the remote past. Visceral leishmaniasis has occurred as early as 3 months (38, 57) and as late as 13 years (58) after transplantation. Reactivation of an old infection, possibly induced by immunosuppressive therapy, is the most frequent mechanism involved in the posttransplant disease. The main clinical manifestations are fever, spleen enlargement and pancytopenia (50). The presenting symptoms are often atypical because anemia and leukopenia may be absent and splenomegaly may develop late in the course of an unnoticed infection (39). Patients may present with fever without other signs; malabsorption caused by infiltration of the gastrointestinal tract can occur and presentation with interstitial pneumonitis, fever and pancytopenia has been reported in a splenectomized kidney transplant recipient (41). The diagnosis can be elusive, and the examination of multiple samples may be needed before a diagnosis can be made (50). The mortality rate in transplant recipients can reach 30%: Bacterial superinfections are the immediate cause of death in reported fatalities. Also relapses and recurrence episodes occur in approximately 30%. Repeated measurement of the spleen has been proposed as both a marker of cure and a predictor of recurrence (50). Post-kala azar cutaneous disease may occur in a subset of patients after treatment of visceral leishmaniasis and has been reported in two transplant recipients (55, 70). Diagnosis: The diagnosis is made by the confirmation of amastigotes in tissue specimens or by the isolation of promastigotes in cultures. Amastigotes in biopsy specimens and aspirates or touch preparations can be observed with the Wright–Giemsa stain (32). The diagnostic yield of skin lesion aspirates, bone marrow aspirates, or aspirates of spleen specimen depends on the parasite species and the culture media. In transplant recipients, the diagnosis is usually made by examination and culture of bone marrow aspirate. In nontransplanted patients, the method's sensitivity approaches 60–80%, but this seems to be higher (approximately 90%) in transplant recipients (50). Repeated sampling may be needed to reach a diagnosis. Liver biopsy; lymph node aspiration or biopsy; and, occasionally, samples from the gastrointestinal tract, lung, or pleura may also lead to diagnosis. When cutaneous and mucosal leishmaniasis are suspected a small wedge or punch biopsy specimen for histopathological examination and culture should be obtained. Touch preparations have a superior diagnostic yield (29). After a parasite has been identified, speciation can be performed through isoenzyme analysis or species-specific monoclonal antibodies. Quantitative or semiquantitative PCR assays have shown a high diagnostic sensitivity in a limited number of patients: They allow for measurement of blood parasitic load, and could be used as surrogate markers of disease activity and response to treatment (34). Anti-Leishmania antibodies have been positive in 92% of transplant recipients with visceral leishmaniasis (34), hence, serology could be used as a first diagnostic approach whenever the disease is suspected. The methods available for antibody detection include the indirect fluorescent antibody test, the ELISA, and a direct agglutination test. Serologic testing cannot differentiate between past or present infections, so results must be carefully interpreted in light of the history and clinical manifestations. ELISA using a recombinant protein antigen (K39) may show a greater specificity (32). Cross reactions with T. cruzi can be seen. Treatment and prevention: Standard treatments for leishmanial infections have been the pentavalent antimony (SbV)–containing drugs, sodium stibogluconate, and meglumine antimonite, at 20 mg SbV per kg body weight for 20–28 days. The common side effects are myalgias, arthralgias, fatigue, malaise, abdominal pain and nephrotoxicity. Serious toxicities are infrequent; they include pancreatitis and cardiac rhythm disturbances (29). Antimonial compounds have an effect on the cytochrome P-450 pathway, so metabolic interactions might lead to high levels of immunosuppressive drugs and close monitoring is necessary to avoid toxicity (44). Most transplant recipients initially treated with pentavalent antimonials have had elevated amylase and lipase levels, with clinical pancreatitis occurring in roughly 25% (51). Liposomal amphotericin B is the only drug licensed for the treatment of visceral leishmaniasis in the United States (71) and is considered the standar