Strongyloides stercoralis, an intestinal helminth, is found in tropical and subtropical regions worldwide. It is an uncommon pathogen in the United States. When it does occur, strongyloidiasis is primarily a disease of immigrants from Africa and Southeast Asia. Historically, transmission in the United States has been reported in proximity to the Appalachian Mountains in southeastern states (1, 2). Typically, the infective filariform larvae, which reside in contaminated soil, penetrate human skin, and then travel through the venous circulation to the lungs where they migrate through the tracheobronchial tree to the pharynx. They are subsequently swallowed into the gastrointestinal tract (3). Unlike most other helminths, Strongyloides can complete an entire life cycle within a single host when filariform larvae enter the venous circulation by penetrating perianal skin or gastrointestinal mucosa. Clinical manifestations in typical hosts range from an asymptomatic carrier state in up to one half of patients to diarrhea, abdominal cramping, nausea, and vomiting in others (4). In asymptomatic carriers, the parasite can persist in the host for decades (3).
Filariform larvae can penetrate through the intestinal mucosa and disseminate to other organs, causing hyperinfection syndrome. Populations at risk include those with hematologic malignancy, stem-cell transplantation, hypogammaglobulinemia, human immunodeficiency virus (HIV), and human T lymphotrophic virus (HTLV)-I in addition to those taking immunosuppressive agents. Transplant recipients can develop severe and atypical manifestations of strongyloidiasis, including rash, ileus, gastrointestinal bleeding, bacteremia, meningitis, liver abscesses, and pneumonia. However, peripheral eosinophilia is often absent in infected transplant recipients (3, 5).
Transmission of Strongyloides by organ transplantation has already been proposed (5, 6). In most cases, donor derivation is difficult to prove whether the recipient is from an endemic region and could have been infected before or after transplantation (7, 8). Donor-derived infection has been most compelling in cases of liver and kidney–pancreas transplant recipients who received organs from a common donor that retrospectively tested positive for Strongyloides antibodies (5). A similar case was also observed in a pancreas recipient (9). It is unknown why certain donors are more likely to transmit strongyloidiasis. We report our experience with donor-derived strongyloidiasis and propose a potentially significant risk factor that may be critical to transmission. The Institutional Review Board at University of Pennsylvania approved this case study.
A 39-year-old woman with a history of end-stage renal disease secondary to hypertension received a deceased-donor renal transplant approximately 10 weeks before presentation. She received a total of five doses of thymoglobulin for induction, and maintenance immunosuppression included tacrolimus, mycophenolate, and prednisone. Approximately 3 weeks before admission, the patient developed a rash on her abdomen. One week before admission, the patient developed nonbloody diarrhea, nausea, vomiting, and intense abdominal cramping.
On presentation, she was afebrile with a pulse rate of 100 beats/min and blood pressure 124/73 mm Hg. The finding of her cardiopulmonary examination was normal, and she had moderate epigastric tenderness to palpation. On dermatologic examination, the patient had two discrete, digitate ecchymotic patches in the periumbilical region (Fig. 1A). Laboratory findings were remarkable for white blood cell count 12,700 cells/μL with no eosinophils and creatinine of 1.31 mg/dL. Skin biopsy of the rash demonstrated larvae consistent with S. stercoralis (Fig. 1B and C), and a microscopic examination of the stool for ova and parasites revealed the presence of Strongyloides larvae as well. Pretransplant serum was negative for Strongyloides antibodies. The patient had never traveled outside the United States in her lifetime, and her most recent travel outside of Philadelphia was to Raleigh, North Carolina. She had not traveled outside the city and never walked outside in bare feet. She had no known close contacts with anyone who may have been infected with Strongyloides before or after transplant. After transplant and before presenting to the hospital, she had not left her home, aside from a single visit to a local restaurant.
Oral ivermectin was initiated at a dose of 200 μg/kg once daily on the first day of hospitalization, but the abdominal cramping and diarrhea became progressively more severe. An upper gastrointestinal barium study with small bowel follow-through was obtained 3 days after initiation of therapy because of progressive symptoms and was remarkable for considerably thickened, irregular folds throughout the entire small bowel consistent with intestinal strongyloidiasis (Fig. 2A).
Approximately 5 days after initiation of therapy, the patient developed rapidly progressive dyspnea and hypoxia, and extensive nodular and ground glass opacities were visualized on a computed tomography scan of the chest. A more focal consolidation was also seen in the left lower lobe (Fig. 2C). Progressive hyperinfection syndrome and concern for malabsorption due to extensive small bowel involvement prompted initiation first of ivermectin enemas and then of subcutaneous ivermectin at 200 μg/kg every other day under an emergency investigational new drug approval. Vancomycin and piperacillin–tazobactam were also added to treat possible superimposed bacterial pneumonia. Subcutaneous ivermectin was continued for a total of 11 days and was converted to oral therapy for an additional 14 days when her gastrointestinal symptoms improved and pulmonary symptoms resolved. Stool was still positive for Strongyloides larvae on the day of discharge, 19 days after admission, but was negative by 35 days.
Because the patient had no risk factors for the acquisition of a primary Strongyloides infection, the donor was investigated as a possible source of infection. The donor was a 54-year-old man from the Dominican Republic residing in the United States for 2.5 years before death as a result of a gunshot wound to the head. The donor fulfilled criteria for brain death approximately 24 hr after admission. The leukocyte count during admission was 14,100 cells/μL with no eosinophils.
A dose of 100 mg of hydrocortisone was administered on day 2, and thyroxine was administered from days 2 to 4. On day 3, the day after the initiation of steroids, the total eosinophil count had increased to 412 cells/μL. On day 4, the day of organ procurement, the total eosinophil count had increased to 523 cells/μL. A dose of 1 g of methylprednisolone was administered on this day for donor preconditioning before procurement, which together with thyroxine as a part of hormonal resuscitation, has been shown in some studies to improve deceased donor stability and to increase organ viability (10, 11). As such, this practice has become a part of routine management of deceased donors in many centers.
Retrospective testing for Strongyloides antibody on banked donor serum by enzyme-linked immunosorbent assay at the Centers for Disease Control (CDC) was positive at 11.7 U/mL (reference >1.7 U/mL positive). The donor had also provided a kidney to a second recipient and a liver to a third patient.
Further investigation revealed that the second kidney recipient was concurrently admitted to the same hospital as the first. She was a 53-year-old woman who had undergone renal transplantation for end-stage renal disease secondary to focal segmental glomerulosclerosis. She also had a history of gastric bypass surgery 8 years before presentation, gastroesophageal reflux disease, and recent pulmonary embolism and deep venous thrombosis on warfarin. She received five doses of thymoglobulin for induction and was subsequently maintained on tacrolimus, mycophenolate, and prednisone. Her travel history was significant for visiting Aruba and Puerto Rico within 5 years.
The initial posttransplant period was uneventful until the day of admission when the patient developed sudden onset of severe epigastric pain radiating to the back followed by several episodes of hematemesis. Admission laboratory examinations were remarkable for a white blood cell count of 9400 cells/μL with no eosinophils, hemoglobin of 8.6 g/dL (previously 10.3 g/dL), platelets of 245,000 cells/μL, and an international normalized ratio of 2. A chest radiograph revealed a patchy infiltrate in the right lower lobe.
Esophagogastroduodenoscopy showed multiple bleeding gastric ulcers, which were injected with epinephrine, resulting in successful control of subsequent bleeding. On the sixth day of admission, the patient was identified as a recipient of a transplanted kidney potentially infected with Strongyloides. At this time, gastric and pulmonary aspirates were microscopically examined for ova and parasites and both were positive for S. stercoralis (Fig. 3A and B). Therapy with oral ivermectin at 200 μg/kg daily for 2 days had been initiated empirically at the time of identification and the patient was retreated weekly for a total of five treatment cycles with oral therapy, because she had no clinical evidence of malabsorption.
Likewise, the patient's stool sample was still positive for Strongyloides larvae at the day of discharge, that is 32 days after admission and 26 days after initiation of treatment, so she was treated with an additional 7 days of daily oral ivermectin with clearance of stool at the end of this period. Diarrhea persisted, which prompted an upper gastrointestinal barium swallow with small bowel follow-through that was consistent with advanced damage due to extensive inflammation and edema from strongyloidiasis (Fig. 2B). Stool ova and parasites have remained negative.
The liver recipient, a 58-year-old man with hepatitis C and history of alcohol abuse, who had been transplanted at another institution, was asymptomatic. His induction immunosuppression was with basiliximab, and the maintenance of immunosuppressive regimen included mycophenolate, tacrolimus, and prednisone. The patient was treated empirically with oral ivermectin 200 μg/kg daily for 2 consecutive days and albendazole 400 mg daily for 7 days. Serology for Strongyloides was 0.84 IU (ARUP laboratories, reference ranges 1.49 IU or less: negative; 1.50–2.10 IU: equivocal; ≥2.11 IU: positive), and microscopic examination of stool for ova and parasites, which was obtained 4 days after initiation of therapy, was negative. A subsequent test for Strongyloides serology 60 days after initiation of therapy and 20 weeks after transplantation was equivocal (1.53 IU).
Time zero biopsies of the transplanted organs were reexamined and no microscopic evidence of Strongyloides was visualized. Serum from both renal transplant recipients and the liver transplant recipient before transplantation were tested at the CDC and were negative for Strongyloides antibodies. Banked donor serum was also obtained and testing at the CDC revealed the presence of IgG antibodies to Strongyloides. Both renal transplant recipients and the donor tested negative for HTLV-I/II and HIV antibodies. The liver recipient tested negative for HIV, but HTLV-I/II was not performed.
Our cases provide definitive evidence for the transmission of Strongyloides by organ transplantation and highlight some of the difficulties in identifying and treating the infection in this population. First, making this diagnosis is especially difficult given the unusual presentations of immunosuppressed patients. In this case specifically, the cutaneous findings were atypical. The majority of published reports of disseminated strongyloidiasis with cutaneous rash demonstrate widespread periumbilical petechial patches, the pathognomonic “thumbprint purpura” sign (12). To our knowledge, this is the first case with limited, subtle cutaneous involvement, with confirmation by skin biopsy. Therefore, physicians should still suspect hyperinfection syndrome even in settings of apparently subtle cutaneous manifestations.
Because of the atypical manifestations of Strongyloides in transplant recipients and the high risk of mortality and morbidity, screening donors and recipients at high epidemiological risk for Strongyloides with antibody testing before transplant would be preferable, so that appropriate treatment can be initiated before development of disease. Ideally, screening should be performed before immunosuppression is initiated. Risk-based donor screening strategies remain a challenge given the diversity of donor origins and exposures and the limited availability of donor history and time for evaluation. Donors and recipients should be considered to be at risk for transmission if they have resided in areas where S. stercoralis is endemic, including the Caribbean, Mexico, and countries of South and Central America, Africa, and Southeast Asia.
Although in many cases, serologic results would not be available before transplant, even delayed identification of donor infection could allow timely initiation of postexposure therapy. The presence of Strongyloides in potential donors should not only necessarily preclude transplantation but also prompt early treatment, particularly because the disease can be rapidly fatal.
Another notable point raised by these cases is that of corticosteroid use in donor preconditioning regimens before organ procurement, which has become a common practice in many transplant centers. It is well established that the use of corticosteroids in patients with Strongyloides infection can precipitate dissemination and hyperinfection, even after a single dose (13). In this case, the previously asymptomatic donor likely reactivated Strongyloides and developed disseminated disease as a result of steroids or acute stress. In addition, kidneys are not sites typically involved in latent disease, implying that dissemination would have been required for transmission to occur.
On the other hand, the use of high-dose corticosteroids as a part of preconditioning regimen in deceased donors alone or in conjunction with triiodothyroxine or l-thyroxine and vasopressin has shown benefit. These benefits include increasing the number of organs recovered per donor from 3.1 to 3.8 (P<0.001) and stabilizing potential donors until organs are able to be procured, thereby increasing the donor pool (10). The benefit to the viability of individual organs recovered from donors receiving triple hormonal resuscitation therapy, however, is questionable. One study showed improved 1-month survival from 92.1% to 96.2% (P<0.01) and decreased rates of early graft dysfunction from 11.6% to 5.6% (P<0.01) (11). However, a recent randomized trial in renal transplant recipients showed no benefit in reduction of incidence and duration of posttransplant acute renal failure (14). The detriment of withholding high-dose corticosteroids for donor preconditioning as measured by a potential decline in the number and quality of the organs likely outweighs the small, although potentially devastating, risk of donor transmission, making risk-based donor screening strategies a more preferable approach.
Even with rapid identification of Strongyloides infection in transplant recipients, treatment can be problematic (3). In immunocompetent hosts, ivermectin has been shown to be more effective than albendazole in uncomplicated stongyloidiasis (15). Consequently, we opted to use ivermectin monotherapy. In most transplant patients with strongyloidiasis, microbiologic clearance of larvae occurs within 21 days of therapy (range 3–21 days) whether using albendazole, thiabendazole, ivermectin, or combinations of these agents (5, 9, 16–30). However, despite multiple courses of treatment, the two patients in this report took 33 and 35 days to clear the parasite, likely due to a combination of impaired immune response, high parasite burden, and malabsorption of the drug. Whether combination therapy with ivermectin and albendazole is superior to monotherapy remains unknown.
Malabsorption can become a distinct barrier to treatment in patients with severe gastrointestinal strongyloidiasis. In these patients, other routes of ivermectin administration, including rectal and subcutaneous, have been used with some success (16–18). Acquiring parenteral ivermectin should be attempted early in the course to avoid potential obstacles to effective treatment. As these cases illustrate, subcutaneous ivermectin may provide a viable alternative to oral therapy in patients with advanced gastrointestinal disease. A parenteral preparation of ivermectin is approved as a veterinary drug. Use of this formulation and route of administration in human patients requires emergency investigational new drug approval from the Food and Drug Administration (Division of Special Pathogens, 301-796-1600). Future development of parenteral ivermectin for human use would be preferable to avoid any delay in therapy. Regardless what therapy is instituted, the doses of immunosuppressive medications should be decreased to the lowest effective dose to minimize the effect of immune suppression on disease severity.
Immunosuppressed patients are also at risk for relapse of strongyloidiasis despite treatment and apparent clearance of the parasite. Reactivation can occur even months after initial treatment (19–21). Some strategies for prevention of relapse have included intermittent monthly therapy or regular monitoring. It is unclear which approach is more effective. However, special attention should be paid to situations in which immunosuppression is intensified such as in times of rejection, and consideration should be made for empiric treatment at these times (21).
Donor-derived strongyloidiasis is not well understood, and it is unclear why some donors transmit infection and others do not. Dissemination of parasites before organ procurement may be required for transmission to occur for certain organs. Although donor preconditioning with high-dose corticosteroids may play a role in dissemination, withholding steroids might decrease the number of organs available for donation in an already sparse donor pool. However, the benefit to individual organs is questionable, and the risks may not be benign, so the use of steroid preconditioning, especially in certain patients, should be further evaluated. Regardless, screening high-risk donors would be a preferable strategy to initiate appropriate therapy in organ recipients before development of potentially fatal disease.
The authors thank LeAnne M. Fox, M.D., M.P.H., Division of Parasitic Diseases and Malaria, Center for Global Health, Centers for Disease Control, for her valuable expertise on Strongyloides; Isabel T. McAuliffe, M.S. and the laboratory at the Centers for Disease control for performing serologic testing; and Paul H. Edelstein, M.D. and the microbiology and pathology laboratories at the Hospital of the University of Pennsylvania for their expertise and preparation of clinical specimens.
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