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Schistosomiasis and Strongyloidiasis Recommendations for Solid-Organ Transplant Recipients and Donors

Camargo, Luis Fernando A. MD, PhD1; Kamar, Nassim MD, PhD2; Gotuzzo, Eduardo MD3; Wright, Alissa Jade MD4

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doi: 10.1097/TP.0000000000002016
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SCHISTOSOMIASIS AND ORGAN TRANSPLANTATION

Introduction and Epidemiology

Schistosomiasis is a geographically restricted disease caused by several species of the trematode worm Schistosoma.1,2 If untreated, it can lead to major disability and death. Typically, only nonspecific symptoms, such as cachexia and anemia occur, but occasionally patients experience more severe complications arising from hepatic (portal hypertension and its related consequences) and urinary involvement. Although in the past few years, preventive measures have reduced the worldwide burden of infection, active transmission still occurs on several different continents.

Almost all cases of human schistosomiasis are caused by 5 species of Schistosoma: S. mansoni (South America, Caribbean, Arabic peninsula, and Africa), S. haematobium (Africa and Middle East), S. mekongi (Laos, Camboja), S. intercalatum (Africa), and S. japonicum (China, Philippines, Indonesia, Thailand). It is estimated that between 200 and 400 million people are infected with any species; however, more than 90% of the cases occur in sub-Saharan Africa.1,2 In Latin America, it is estimated that between 1 and 3 million people are infected with S. mansoni.3 Because this is the only species naturally occurring in Latin America, it will be the focus for the remainder of the article. The vast majority of these cases occur in Brazil,3 where S. mansoni is endemic. Transmission occurs in 19 of Brazil's states, particularly those in the Northeast region.4 Efforts to control schistosomiasis have been carried out in Brazil since 1975; despite this, the transmission area has expanded to previously unaffected urban and coastal locations over the last few decades.5

Parasite Characteristics

The life cycle of Schistosoma requires both a definitive host and an intermediate host. Adult worms live in the mesenteric vessels (S. mansoni, S. mekongi, S. intercalatum, and S. japonicum) or the vesical plexus (S. haematobium) of humans, the definitive host. After sexual reproduction, viable eggs move to the feces or urine and then to the environment. In fresh, warm water, under ideal light conditions, the larva form miracidium from the eggs. These miracidia then swim to penetrate the skin of their intermediate hosts, specific species of snails endemic to each region. For S. mansoni, the intermediate hosts are species of Biomphalaria. Within the intermediate host, 2 generations of sporocytes are produced before finally emerging as cercaria to be eliminated again into the fresh water. These cercariae are free-swimming forms, which in turn infect human through intact skin. This completes the life cycle. Soon after entering the human body, the cercariae become schistosomules that migrate until they reach the mesenteric or vesical plexus (Figure 1).1,2

FIGURE 1
FIGURE 1:
Life cycle of Schistosoma spp. Source: Centers for Disease Control and Prevention. Parasites: Schistosomiasis—Biology.6

General Manifestations

Disease related to Schistosoma infection can occur either immediately after acute infection or later because of chronic infection. In acute disease (Katayama fever), symptoms and signs are nonspecific—high fever, urticarial lesions where cercariae entered the skin, eosinophilia, and other laboratory signs of systemic inflammation.1,2 This can make diagnosis difficult. If not properly diagnosed and treated, a chronic inflammatory state may ensue related to the continuous presence of the infecting organisms and the release of specific antigens. This can result in anemia, malnutrition, cognitive impairment, and end-stage organ function.

Chronic consequences of schistosomiasis are mostly because of the host’s inflammatory response to the presence of eggs. The eggs themselves are also hepatotoxic. Eggs which do not pass out of the body can become lodged in other organs. Granuloma formation and fibrosis then result from the inflammatory response mediated by CD4 cells and a variety of cytokines.7 In species other than S. haematobium, the major site for egg deposition is the liver. Here, granuloma formation often traps the eggs in the small portal venules causing hepatomegaly, which is seen most commonly in children. After years of disease, fibrosis develops in the periportal spaces (“clay-pipe stem” fibrosis) causing obstruction of portal blood flow. This results in portal hypertension, which then leads to splenomegaly and hypersplenism as well as the formation of collateral blood vessels (ie, esophageal varices). Once these collaterals develop, the eggs can then migrate to other circulatory beds such as the pulmonary circulation where they can cause further end organ dysfunction related to fibrosis (eg, pulmonary hypertension and cor pulmonale). Characteristically, liver function is preserved, except when other diseases occur concomitantly, such as chronic hepatitis B.7

Rarely, neurological complications occur because of egg deposition in the brain and spinal cord with subsequent inflammation. This is typically an early complication. Neurological complications of cerebral schistosomiasis include delirium, loss of consciousness, seizures, dysphasia, visual field impairment, focal motor deficits, and ataxia.8

Diagnosis

Microscopic examination of the stool and urine for ova and parasites is the gold standard method for diagnosis of Schistosoma infection. There are several reasons why this test is imperfect. Egg laying in intestinal and urinary Schistosomiasis starts 6 weeks and 90 days after cercarial infection, respectively.9 Hence, the direct egg detection tests are not appropriate for early diagnosis of disease. In patients with liver disease, microscopic examination can also be insensitive unless a concentration technique like the Kato-Katz method is used, or the testing is repeated.

Serological tests are mainly directed against antigens for S. mansoni that only cross-react with another species. Nevertheless, they still can be used for the diagnosis of infection for any patient. Different assays are available such circumoval precipitin test, the indirect hemagglutination assay, and various enzyme-linked immunosorbent assays.9,10 These assays are highly sensitive but only moderately specific. They can be considered an excellent tool for screening patients in endemic areas. However, antibodies can remain detectable for long periods after treatment, and consequently, serological tests do not differentiate between active or past infection. In immunosuppressed patients, seroconversion can be delayed or never occur further complicating the picture.11

In cases where there is clinical evidence suggestive of Schistosomiasis without any confirmation by standard diagnostic testing, tissue biopsies can be performed. Schistosoma eggs can then be identified in the tissue to make the diagnosis. Because eggs can persist after successful treatment, you need a well-experienced technician to read the specimen. In the rectal biopsy in particular, a well-experienced technician can characterize the eggs as immature or mature as well as living or dead.12,13 Egg viability studies as well as the microscopic examination for the movement of flame cells can also be performed to determine active versus past infection. Although it is not yet widely available, polymerase chain reaction (PCR) technology represents a promising new tool for diagnosis of both acute and chronic infection.9

Finally, there are several nonspecific tests which may be helpful for infected patients. Imaging studies, such as ultrasound, can demonstrate periportal fibrosis or other complications of chronic infection. It is currently not known what the role is for the noninvasive radiologic techniques (eg, fibroscan) to assess hepatic fibrosis among infected patients. This should be further investigated, particularly in endemic areas. If present, eosinophilia can be used as a crude marker of infection and successful treatment.14

Treatment

First-line therapy for schistosomiasis is oral praziquantel, given at a dose of 20 mg/kg per dose 2 or 3 times daily, for 1 day. S. mekongi or S. japonicum infection require a higher dose (60 mg/kg per day total) than S. mansoni or S. haematobium (40 mg/kg per day).11 Oxamniquine and antimalarial artemether can be used as alternative therapies. More than 60% of patients are cured after a first course of treatment; if not, then therapy can be repeated or an alternative therapy can be used.9 Praziquantel achieves cure rate of 60% to 70%.15 Artemisinin derivatives a worm reduction rate ranging from 50% to 100%.16

Microscopy can be used to confirm treatment success. If treatment is unsuccessful, temporary suspension of oviposition by female worms can occur. In this case, microscopy of stool and urine must be repeated at least monthly from 4 months to 1 year after treatment to ensure eradication.

Prevention

Schistosomiasis prevention strategies have succeeded in dramatically reducing the global burden of disease. Large-scale measures have focused on the improvement of sanitary conditions—such as preventing infected patients from excreting viable eggs in water reservoirs—as well as eliminating the intermediate host using molluscicides (mainly niclosamide). However, some countries have not been able to successfully implement these measures. In such countries, regular mass-treatment of patients at risk, thus reducing the transmission burden, is often used with success.17 Complete eradication will depend on multifocal interventions, involving health education practices (such as avoiding contact with contaminated water) as well as mass treatment with praziquantel.18

Schistosoma Management in the Solid Organ Transplant Setting

Organ Donors Infected by Schistosoma

The transmission of Schistosoma infection via an allograft can cause infection after solid organ transplantation. However, organs from Schistosoma-infected donors living in schistosomiasis endemic areas have been given to both Schistosoma-infected and noninfected recipients with success.11,19-21

Liver allografts obtained from Schistosoma-infected donors have been intentionally or accidently transplanted.11,20-23 Overall, published data suggest that the risk of Schistosoma transmission via the liver organ is low. In most cases, schistosomiasis was not diagnosed in the donors before transplantation because they were asymptomatic and any predonation tests for parasitic disease were falsely negative or not done. Instead, the diagnosis of schistosomiasis was often made based on a peri-implant liver biopsy or from liver explant findings, which showed a granulomatous reaction and S. mansoni eggs. It was occasionally confirmed by serological tests performed on the donors' blood obtained before donation.

Although data remain controversial on whether schistosomiasis worsens the clinical outcome of hepatitis C virus infection,11 the long-term outcomes of most liver-allograft organs infected with Schistosoma are excellent.19 Therefore, it has been suggested that the presence of eggs in a liver biopsy, in the absence of any other liver complications, should not preclude organ donation.

Screening for donors from endemic areas is recommended, even if they have immigrated to a nonendemic country as the worms can live for up to 5 years. If a positive result is available before transplantation, organs for donation should not be discarded.11,20-22 Instead, infected donors should be treated before donation with a single dose of praziquantel if feasible. If not, then the organ should be accepted and the recipient closely monitored for complications. Monitoring can include doing stool microscopy for Schistosoma eggs or serology for seroconversion (Table 1). Preemptive treatment of recipients remains controversial as praziquantel has no effect on the eggs or the immature worms that are usually found in the liver. The adult worms (schistosomes)—found in the mesenteric plexus—are typically not part of the tissue transplanted. Even if they are, these adult worms do not replicate within the host. Hence, only nonreplicating adult worms can be transmitted, and these usually die within 3 to 5 years. Only if active egg excretion or seroconversion is found should recipients be treated with praziquantel posttransplant.

TABLE 1
TABLE 1:
Recommendations for screening of organ transplant donors for schistosomiasis

Organ Recipients Infected by Schistosoma

In addition to the risk of donor-derived Schistosoma infection, organ transplant recipients can either present with a de novo infection or have reactivation of a previous infection. Very few documented cases of de novo schistosomiasis have been published. Hepatic or intestinal schistosomal infections have been observed after liver transplantation.24-26 In these cases, it is unknown whether the infection represented reactivation of a previous infection in the setting of immunosuppression or if they were caused by a reinfection.24 In a 15-year, single-center study, no recurrence of schistosomiasis was observed in patients who had received a liver transplant because of liver complications from previous schistosomiasis. Moreover, in this series, the long-term survival of patients and allografts was similar to those who had received a transplant for other reasons.27 In this center, liver transplant candidates were screened for the presence of schistosomal antibodies with the circumoval precipitin test. Patients who were suspected of having active schistosomiasis underwent a stool analysis for Schistosoma eggs and a rectal biopsy if that was negative. Patients with active Schistosoma infection were treated with a single dose of praziquantel before transplantation and were instructed to avoid exposure to water contaminated with Schistosoma.27

Controversial data regarding the outcome of kidney transplantation in patients infected by S. haematobium have been reported. Some studies reported recurrence of schistosomiasis-associated nephropathy.28-31 Others suggest that this can be successful.

We recommend that all transplant candidates originating from endemic areas be tested for schistosomiasis. Transplant candidates with schistosomiasis should be promptly treated before transplantation because praziquantel may not work as well in an immunosuppressed patient. Treated candidates should then undergo follow-up testing to ensure eradication with repeated treatment if necessary. Uninfected transplant candidates and recipients travelling to endemic areas should strongly be advised not to bathe in fresh water reservoirs (Table 2).

TABLE 2
TABLE 2:
Schistosomiasis general preventative measures and specific preventive measures in organ transplant donors and recipients

Among travellers returning from endemic settings, serological tests are a powerful tool for the detection of schistosomiasis (Utzinger et al, CMI2015).

STRONGYLOIDIASIS AND ORGAN TRANSPLANTATION

Introduction and Epidemiology

Strongyloidiasis is a worldwide infection caused by the intestinal nematode or roundworm Strongyloides stercoralis. Transmission occurs by penetration of filariform larva through intact skin. Most infected patients are asymptomatic; however, children can exhibit pulmonary symptoms and immunocompromised patients are at risk of life-threatening dissemination in the setting of immunosuppression.

Conservative data estimate that 30 to 100 million patients are infected with Strongyloides, mainly in Africa, Asia, and Latin America. Accounting for these inaccurate detection methods because of underdiagnosis and poor reporting, the real number may be from 100 to 370 million infected patients worldwide.32 In the Americas, estimates vary dramatically depending on the diagnostic method employed and the population stratum studied, but high infection rates (eg >20%) have been recorded in studies from Brazil, Peru, Venezuela, Argentina, and Ecuador.33

Parasite Characteristics

Strongyloides has a life cycle that is like other helminthic worms (Figure 2). Female worms deposit their eggs in the bowel. These eggs are generated by parthenogenesis, because there are no adult male worms infecting the human bowel. Eggs then become noninfectious rhabditiform larvae, which are eliminated to the environment within the feces. Under ideal soil conditions, the rhabditiform larvae proliferate and transform into filariform larvae, which then infect humans by penetrating intact skin. This typically occurs through the foot; although this may be primarily because of walking in unsanitary areas, S. stercoralis is strongly attracted by urocanic acid, a histidine metabolite in the skin, which is found at 5 times the concentration in the foot.35 After penetration, they undergo systemic migration to the lungs where they can be swallowed allowing them to reach the small intestine. Filariform larvae may also migrate directly to the small bowel via connective tissue without passing through the lungs. A feature of S. stercoralis is the high rate of autoinfection. Some rhabditiform larvae may transform into filariform larvae while they are still inside the intestines. These filariform larvae then penetrate the colonic mucosa or perianal skin, initiating the life cycle again while entirely within the host. This unique feature of the S. stercoralis life cycle explains why there are infections that persist for years to decades after patients leave endemic regions.36

FIGURE 2
FIGURE 2:
Strongyloides stercoralis life cycle. Source: Centers for Disease Control and Prevention. Parasites: Strongyloides—Biology.34

General Manifestations

Strongyloidiasis ranges from acute/chronic strongyloidiasis to hyperinfection syndrome (HS) and disseminated strongyloidiasis (DS). In experimental studies, patients do get symptoms during the acute phases including rashes at the site of skin penetration, cough, abdominal cramping, and diarrhea.37 Once the autoinfective cycle of chronic strongyloidiasis begins, the majority are asymptomatic, and diagnosis typically occurs during a workup for unexplained peripheral eosinophilia or screening before immunosuppression.

Patients with DS are often critically ill. They can have organ dysfunction from the migration of the parasite to atypical sites such as the skin, liver, kidney, or central nervous system. These are sites not involved in the natural life cycle of the worm. Superimposed bacterial infections such as meningitis can develop from the translocation of gut flora with the invading worms.38 At the extreme, patients have shock, and multiorgan failure leading to death. HS represents a higher burden of disease in sites normally involved with the worm life cycle. It falls in between the 2 extremes with symptoms like acute strongyloidiasis—persistent abdominal cramping or diarrhea—or that of DS—ileus, obstruction, or disseminated pneumonia or even diffuse alveolar hemorrhage—depending on how advanced the disease process is. Immunosuppression—particularly corticosteroid use—is the main risk factor for development of HS/DS.39

Diagnosis

Because most patients with chronic strongyloidiasis are asymptomatic, symptoms alone cannot be used as a screening method. The same can be said for using eosinophilia as a marker of infection. Eosinophilia can be intermittent in chronic infection and even disappear with HS/DS disease.40

Moreover, corticosteroid therapy promotes eosinophil apoptosis reducing the value of this marker further in the immunosuppressed host.41 The most common method for both screening and diagnosis is direct microscopy on the stool for parasites. Shedding can be intermittent, particularly during chronic infection, with reported sensitivities of a single specimen ranging from 0% to 66%.42 Samples should be repeated if there is a high suspicion of infection. The yield can also be increased using concentration techniques such as the Baermann method or Koga Agar Plate.43

Endoscopic examination with aspiration or biopsy can also establish a diagnosis. In patients with HS/DS, respiratory secretions, urine, ascitic fluid, and CSF are possible sites of infection and should be examined in the appropriate clinical context. HS has an increased parasite burden within the respiratory or gastrointestinal tract while DS is diagnosed with positive specimens outside these 2 sites.40

Commercial serologic tests are also available, enzyme-linked immunosorbent assays for Strongyloides immunoglobulin G (IgG) antibodies are the most frequently used. These are highly sensitive (70-97%) and specific (87-100%).44 Patients can get false-positive reactions due to other nematodes making interpretation in certain regions difficult as this reduces the specificity and positive predictive value of the test; patients may also have persistent antibodies after successful therapy limiting the value of this test in the diagnosis of repeat infections.45 Patients can get false-negative reactions in the setting of immunosuppression.46 Because the consequences of untreated S. stercoralis in the setting of immunosuppression are severe, repeated serology or presumptive therapy is justified if there is a high suspicion of infection or the patient resides in a (hyper)endemic area.

There is a lot of interest in developing new assays to improve on the limitations of current diagnostic testing mechanisms. This includes using novel recombinant Strongyloides antigens (eg, NIE) to improve on the specificity of the test or novel platforms (eg, luciferase immunoprecipitation system or LIPS) to improve on the turnaround time or value as a test of cure.43 PCR is another of the promising new diagnostic techniques but it is also not immune to issues around limited sensitivity nor is it widely available at the present time.43 More research into this area is urgently needed.

Treatment

The first-line recommended treatment regimen for chronic strongyloidiasis is ivermectin 200 μg/kg po daily for 1 to 2 days. From animal studies, ivermectin appears to be effective against both the adult and larval forms of S. stercoralis; however, its efficacy is limited to those parasites found in the intestinal stages so cure rates have been less than a 100%.47,48 Therefore, some clinicians repeat therapy at 2 weeks (the duration of 1 autoinfection cycle).49 Most patients tolerate ivermectin for short-term therapy without significant side effects or toxicity. Ivermectin is a p-glycoprotein substrate; therefore, tacrolimus and other p-glycoprotein inhibitors may increase the concentration or distribution of ivermectin in the body.50 This is the only drug interaction of concern with the commonly used immunosuppressants. An alternative treatment is albendazole, but cure rates are lower.51

There is not a well-defined treatment algorithm for patients with HS/DS. Recommendations range from daily oral ivermectin for 5 to 7 days to daily treatment until symptoms improve and serial stool samples are negative for 2 weeks.52 In the setting of ongoing immunosuppression or heavy parasite burden, longer durations are favored because there is a higher risk of treatment failure. In severe cases, combination ivermectin and albendazole can be given. Alternative forms of ivermectin, including intravenous or veterinary preparations, have also been successful.53 Patients should be given appropriate adjunctive measures including antibiotics for secondary bacterial infections, intravenous fluid resuscitation, and/or ventilatory support. Patients with HS/DS are highly infectious and should be isolated appropriately.

Cure should be documented if possible. This may require repeated stool examinations given the intermittent shedding in chronic infection. If antibody tests were used to confirm the diagnosis, a fall in the titre can be used to confirm eradication.46 However, a uniform threshold for cure using this method has not been defined.43 At present, no single test conclusively proves cure and patients may have to be followed for 1 to 2 years after therapy to ensure relapse does not occur. If eradication is not achieved, repeat treatment and testing for human T cell lymphotropic virus (HTLV-1) is advised.49

Prevention

As with other roundworm infections, prevention and control of strongyloidiasis is difficult. Strategies aimed at eliminating the nematode from asymptomatic shedders with periodic treatment cycles have logistic implications and results are not universally accepted. Education and basic sanitary conditions to avoid patients defecating in the soil play a significant role. Finally, the use of shoes in areas of known transmission and high prevalence is important.

Strongyloidiasis Management in the Solid Organ Transplant Setting

Organ Donors Infected by Strongyloides

S. stercoralis transmission by an infected organ donor has been well documented; unfortunately, this is not an infrequent situation.54 The highest risk for transmission might be thought to be intestinal or pancreatic transplants as these organs are involved in the life cycle of Strongyloides; however, transmission has been documented in recipients of all major organ groups. Recently, the Centers for Disease Prevention and Control described 7 separate donor transmissions by transplanted organs. Six of these donors were from Latin American Countries. A total of 11 of the 20 recipients were symptomatic because of Strongyloides, and 2 of them died from severe strongyloidiasis.55

High-risk donors, such as those who were born or those who have lived in endemic areas for a significant period, should be screened for S. stercoralis infection before donation (Table 3). Screening can be done via stool or serology or both depending on the resources available and the constraints given the type and urgency of transplantation (eg, living vs deceased donors).

TABLE 3
TABLE 3:
Recommendations for strongyloidiasis donor screening

Living donors should complete screening and, if necessary, therapy before donation if possible. Because the rate of eradication is not 100%, ideally recipients should also be prescribed preemptive treatment with ivermectin (1- to 2-day course as for infected patients, starting whenever the patient can receive oral medications) after transplantation with follow-up screening to ensure eradication in nonendemic settings. Treatment of the recipient alone after transplantation could also be used in situations where donors decline therapy or if time constraints result in test results not being available before transplantation.

Test results are unlikely to be available before transplantation in most cases of deceased donors. This should not delay transplantation; instead recipients should be treated after transplantation if the donor testing comes back positive. This practice has proven effective according to the New York Donor Network experience.55

When a diagnostic workup is not feasible because of time constraints or diagnostic testing issues, such donors could either be empirically treated before transplantation and/or the recipient be given prophylactic treatment after transplant. In hyperendemic areas with wide access to ivermectin, including most Latin American countries, donors and recipients could receive a single dose of universal prophylaxis, considering low-cost and low drug toxicity.

Organ Recipients Infected by Strongyloides

Patients who are transplanted with untreated S. stercoralis infection are at high risk of HS/DS because of their immunosuppression. Patients who have emigrated from or lived in an endemic region should be screened before the onset of immunosuppression as the rate of detection can be high.56 Veterans who fought in endemic countries are also at risk. As the infection can last decades, there is no time limit on how long it has been since exposure.49 Screening should include a check for eosinophilia and at least 1 stool specimen for ova and parasites. In nonendemic settings, an antibody test may be helpful. In certain regions of the world, testing for HTLV-1 should also be done, as HTLV-1–positive patients are more likely to fail therapy.57

Transplant candidates who are found to be infected should be treated before transplant. In (hyper) endemic regions or in places where treatment is easily accessible, centers may choose to treat all candidates before transplant without screening because there is a risk of false-negative testing. In these same regions, retreatment is offered to recipients who are treated for rejection as there have been cases of reactivation in this setting. Posttransplant, there are 2 options: surveillance stool exams may be done on a routine basis (eg, annually) with repeated therapy given for positive results or repeated courses of ivermectin for prophylaxis may be given at predetermined intervals.56 Prophylaxis may also be necessary for HTLV-1–positive patients in nonendemic settings as they are at high risk of relapse even with therapy. The optimal strategy depends on local epidemiology, laboratory capabilities, and drug availability.

There is a very small risk of acquisition of S. stercoralis with most leisure or business travel.58 The risk is highest in recipients who stay for prolonged periods (>3 months) in endemic regions. Travellers who visit friends and relatives fall into this category as they may not seek pretravel advice and may stay in more remote settings.59 The best measure for preventing infection with S. stercoralis is to wear shoes in endemic areas, particularly where there is inadequate human waste disposal (Table 4).

TABLE 4
TABLE 4:
Strongyloides preventive measures in organ transplant donors and recipients

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