© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd Transplant Infectious Disease, ISSN 1398-2273
Case report
Strongyloides stercoralis infection in allogeneic stem cell transplant: a case report and review of the literature A.P. Iori, A. Ferretti, G. Gentile, S. Gabrielli, S. Perrone, W. Barberi, G.F. Torelli, F. Natalino, E. Scalzulli, V. Totino, R. Foa, G. Cancrini, C. Girmenia. Strongyloides stercoralis infection in allogeneic stem cell transplant: a case report and review of the literature. Transpl Infect Dis 2014: 16: 625–630. All rights reserved Abstract: Strongyloides stercoralis infections may be documented in low-endemicity areas, particularly in immigrants from endemic areas. The case of a patient from Bangladesh, an immigrant to Italy who developed a S. stercoralis infection after allogeneic stem cell transplant, is described, and 7 further cases are reviewed. Because of the atypical clinical presentation, the low predictive role of the eosinophil count, and the low sensitivity of the microbiological tests, diagnosis of strongyloidiasis is a challenging problem. When a case of S. stercoralis infection is suspected, previous exposure may be the only clue to guide the diagnostic approach.
A.P. Iori1, A. Ferretti1, G. Gentile1, S. Gabrielli2, S. Perrone1, W. Barberi1, G.F. Torelli1, F. Natalino1, E. Scalzulli1, V. Totino2, R. Foa1, G. Cancrini2, C. Girmenia1 1
Dipartimento di Ematologia, Oncologia, Anatomia Patologica e Medicina Rigenerativa, Azienda Policlinico Umberto I, Sapienza University, Rome, Italy, 2Dipartimento di Sanita Pubblica e Malattie Infettive, Azienda Policlinico Umberto I, Sapienza University, Rome, Italy Key words: Strongyloides stercoralis; allogeneic stem cell transplant; immigrant; parasitological screening Correspondence to: Anna Paola Iori, Dipartimento di Ematologia, Oncologia, Anatomia Patologica e Medicina Rigenerativa, Azienda Policlinico Umberto I, Via Benevento 6, 00161 Rome, Italy Tel: 39-06-857951 Fax: 39-06-44241984 E-mail: [email protected]
Received 11 December 2013, revised 31 January 2014, accepted for publication 18 February 2014 DOI: 10.1111/tid.12239 Transpl Infect Dis 2014: 16: 625–630
Strongyloides stercoralis is a nematode, endemic in tropical and subtropical regions. Considering that it survives in small areas of low endemicity at colder temperate climates, and that it can persist for decades after the initial infection in immigrants from endemic areas, strongyloidiasis is currently considered as a possible cause of helminth infection worldwide (1). Infection occurs when the infective larvae present in the soil penetrate the naked skin, enter the blood vessels, are carried to the lungs, and migrate, via the respiratory tree, to the pharynx, completing their life cycle to adult worm in the intestinal tract (1). The parasite may cause asymptomatic infections in half of
the affected patients, or a chronic disease that can be characterized by mild pulmonary and gastrointestinal (GI) symptoms, or severe manifestations including ileus and GI bleeding. Intermittent eosinophilia can be observed and only specific serology and parasitological analyses, applied to stool specimens, duodenal content, and/or bronchoalveolar lavage fluid, can confirm the infection (1). In immunocompromised hosts, such as transplant recipients, the infective potential of the parasite is increased. Larvae may migrate through the bowel wall, travel through the venous system to the lungs, but also disseminate to every tissue of the body, in the context of continuous autoinfective internal
625
Iori et al: Strongyloidiasis in allogeneic stem cell transplant
cycles. This dissemination can produce a potentially fatal acute respiratory distress syndrome-like picture, also named hyperinfection syndrome (HS). Transplant recipients may develop S. stercoralis disease, as a progression of the chronic intestinal strongyloidiasis present before transplantation or following an allograft transmission (2–4). Here, we describe the case of a S. stercoralis infection diagnosed in a patient from Bangladesh who received an allogeneic stem cell transplant (allo-SCT) at our center in Rome. The cases reported in literature, the clinical aspects, and specific recommendations regarding prevention, diagnosis, and treatment of strongyloidiasis in allo-SCT recipients are reviewed.
Case report A 35-year-old man, born in Bangladesh where he lived until the age of 20 years, and where he returned periodically, immigrated to Italy in 1998, where he was diagnosed with acute lymphoblastic leukemia in April 2012. Six months after the achievement of complete remission with standard chemotherapy, he experienced leukemia relapse and obtained a second remission with salvage chemotherapy. In February 2013, he underwent an allo-SCT from his haploidentical brother. The pre-transplant conditioning regimen consisted of 12 Gy total body irradiation and fludarabine. Graft-versus-host disease (GVHD) prophylaxis included the standard cyclosporine, mycophenolate mofetil, and cyclophosphamide. On day +2, he developed fever and empiric piperacillin-tazobactam
plus tigecycline treatment was started. Subsequently, other antimicrobial drugs (meropenem, daptomycin, and liposomal amphotericin B) were administered because of a persistent febrile neutropenia in spite of the good clinical condition of the patient and the absence of any infectious clinical and laboratory signs. The engraftment was observed on day +17. On day +29, while remaining febrile, the patient started to present diarrhea, nausea, vomiting, asthenia, and, sporadically, generalized widespread itching. On day +37, a quick increase of eosinophils (2700/ mm3) was observed and a parasitological examination of the stools was requested. Direct smear evidenced rhabditiform non-infective larvae of S. stercoralis (Fig. 1) and Ridley concentration allowed calculation of the presence of 240 larvae/g of feces (5). Very sensitive commercial serological enzyme-linked immunosorbent assay testing applied to identify antibodies (immunoglobulin-G), specifically reacting with Strongyloides ratti somatic larval antigens (Bordier Affinity Products SA, Crissier, Switzerland), in this case proved negative. No signs or symptoms of parasitosis or peripheral blood eosinophilia had been reported in the clinical history. Parasitological stool analyses and serological investigations of his brother proved negative. Therapy with albendazole 400 mg twice a day (25 mg/kg) was started; fever disappeared after 2 days, and the patient’s clinical conditions promptly improved. After 10 days of therapy, search for the parasite was negative in 3 consecutive stool specimens. Albendazole was stopped after 20 days of treatment. The patient was discharged with complete resolution of
A
B
Fig. 1. (A) Microscopic examination of the stool sample shows at least 5 rhabditiform larvae (arrows), which measure up 380 lm long by 20 lm wide, among normal specimen debris. (B) Strongyloides stercoralis rhabditiform larva. Gray arrow indicates the packet of cells that are the genital primordium of the future adult nematode, which is fairly obvious and can be seen about two-thirds of the way back from the anterior end. The other important morphological key element to recognize this larva is the length, extremely short, of the mouth opening (only a few micrometers), clearly apparent on top of the cephalic end (black arrow).
626
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Iori et al: Strongyloidiasis in allogeneic stem cell transplant
the signs and symptoms previously reported, and a persistent normalization of the eosinophil count. A further search for the parasite performed after 4 months was negative.
Review of the literature and discussion A systematic review of the literature was performed by PubMed search limited to English–language articles. Including our present case, only 8 cases of strongyloidiasis in allo-SCT recipients have so far been reported to our knowledge (Table 1) (6–12). All were adult patients with hematological diseases (median age 36 years, range 33–54). The patients received their transplants in centers in America (4 patients), Europe (3 patients), and India (1 patient). All but 1 patient were from S. stercoralis-endemic areas and the remaining German patient, with an infection documented in the urinary tract, was a truck driver whose regular trucking route was between northern and southern Europe (10). Only 2 patients presented eosinophilia with clinical signs possibly related to the S. stercoralis infection before transplantation, but pre-transplant screening failed to detect the parasite; in the other 6 patients, the pre-transplant history was unremarkable. Median time for the development of signs of strongyloidiasis was 21 days after transplantation (range 2–64). The disease presented as HS in 4 cases, focal GI symptoms in 3, and urinary tract localization in 1; only our patient developed eosinophilia. Five patients died, but the parasitic infection was considered the cause of death in 3 cases (all with HS). The 3 patients who survived (including a patient with HS) were all receiving cyclosporine as GVHD prophylaxis. Strongyloidiasis is an uncommon disease in allo-SCT patients, but it is associated with a poor prognosis, especially when it evolves into a HS (6, 8, 12). Strongyloides species immunoglobulin-G enzyme-linked immunosorbent assay testing is recommended for patients from endemic areas or for patients with GI symptoms or eosinophilia before the transplant (13). Serological testing of strongyloidiasis is quite reliable and widely used, but negative results may be expected in immunocompromised subjects. Stool screening is recommended when serological testing is unavailable, or when serological findings are negative in patients with significant symptoms, eosinophilia, or a history of exposure, especially in immunocompromised patients who can have false-negative tests. At least 3 consecutive stool examinations should be performed, in view of the higher sensitivity (70%) compared with that of a single
stool examination (30%) (1). Finally, polymerase chain reaction-based techniques can be applied at some research laboratories to improve the diagnostic sensitivity. A major problem in the pre-transplant screening for S. stercoralis is represented by the frequent lack or low specificity of the clinical manifestations of infection including eosinophilia, which can be transitory or absent. Furthermore, considering that S. stercoralis can persist in the human host for decades after the initial infection, the data of earlier transitory signs suggestive for a parasitic infection can escape the pretransplant clinical history. While parasitological screening is a standard in transplant centers located in endemic areas, it may not be performed in lowendemicity areas, where knowledge of the clinical and epidemiological findings of this infection is limited. Although our patient was a native of Bangladesh, an area with a very high prevalence of S. stercoralis infections (14), we did not include a parasitological examination in the pre-transplant screening. The diagnosis of strongyloidiasis after transplantation is another challenging issue. Failure to detect larvae in a stool examination and negative immunodiagnostic assays do not necessarily indicate the unequivocal absence of the infection (1–4). Signs and symptoms of GI disease may mimic other post-transplant intestinal complications, including other infections, drug toxicity, and acute GVHD. Furthermore, intestinal acute GVHD and S. stercoralis infection may occur at the same time (7, 11). HS may be misdiagnosed or associated with other infections, and microscopic examination of the respiratory secretions may lead to an incidental recognition of S. stercoralis. With the exception of our patient, who developed a marked eosinophilia, in the other cases of S. stercoralis infection in allo-SCT recipients no abnormal eosinophil count was observed. Therefore, for post-transplant diagnosis of S. stercoralis infection, the exposure history, more than the clinical and/or laboratory findings, should guide the parasitological work-up. Our patient received albendazole treatment (the only drug immediately available at that time), with prompt disappearance of fever and of other signs and symptoms of the infection and rapid fecal clearance of the parasite. However, it should be underlined that ivermectin is the first-line therapy, as it is more effective and better tolerated than thiabendazole or albendazole for the treatment of strongyloidiasis (4). Of interest, cyclosporine may have a protective effect in S. stercoralis infection, as suggested in animal models (15). Three patients who were receiving cyclosporine as prophylaxis of GVHD concomitantly with the
Transplant Infectious Disease 2014: 16: 625–630
627
628 No
Yes, gut (21)/Yes
21
Nausea, vomiting, epigastric pain, bloating
NR
NR
NR
NR
NR
NR
NR
Pulmonary hyperinfection
Signs possibly related to SS infection before transplantation
Eosinophilia before transplantation
Screened before transplantation
Conditioning/type of donor
Cyclosporine as GVHD prophylaxis at the time of SS infection
GVHD diagnosis, site (day from allo-SCT)/steroid treatment
Timing of SS infection, days after transplantation
Clinical signs of parasitosis post transplant
Non-myeloablative/ unrelated
Yes, negative
Yes
Systemic respiratory symptoms
Idiopathic hypereosinophilic syndrome
Multiple myeloma
Underlying disease
Texas-Louisiana/ Texas
M/54
Qazilbash et al. (7)
NR/Texas
NR
Safdar et al. (6)
Site of origin of the patient/site of transplant center
Gender/age in years
Author (Reference)
Transplant Infectious Disease 2014: 16: 625–630 Abdominal pain, diarrhea
Hematuria, suprapubic pain Diarrhea, nausea, pulmonary hyperinfection
Fever, bloody diarrhea, pulmonary hyperinfection
Abdominal pain, bloody diarrhea, jaundice. Pulmonary hyperinfection
64
No/
Yes, gut (15)/Yes
15
No
Reduced intensity/NR
No
No
No
Myelodysplastic syndrome
Bolivia/Spain
M/36
Izquierdo et al. (12)
Yes
Myeloablative/sibling
No
No
No
Acute lymphoblastic leukemia
India/India
M/33
Oberoi et al. (11)
2
Yes (3 months after albendazole therapy)/NR
NR
Myeloablative/ NR
No
No
No
Chronic myeloid leukemia
Germany/ Germany
M/38
Steiner et al. (10)
54
No/Yes
Yes
Myeloablative/ sibling
No
No
No
Acute lymphoblastic leukemia
Brazil/Brazil
M/35
Dulley et al. (9)
2
No/No
No
Myeloablative/ unrelated
Yes, negative
Yes
Nausea, abdominal pain
Acute myelomonocytic leukemia
Florida/Florida
F/44
Wirk & Wingard (8)
Reported cases of strongyloidiasis in allogeneic stem cell transplant patients
Diarrhea, vomiting
29
No/No
Yes
Myeloablative/ haploidentical
No
No
No
Acute lymphoblastic leukemia
Bangladesh/ Italy
M/35
Iori et al. (Present case)
Iori et al: Strongyloidiasis in allogeneic stem cell transplant
Died 20 days after SS disease onset (multiorgan failure. At autopsy no larvae in tissues)
No
Ivermectin, Thiabendazole (No)
No
Duodenal biopsy
Qazilbash et al. (7)
Died 11 days after SS disease onset (SS hyperinfection)
Klebsiella pneumoniae and Enterococcus species septicemia
Ivermectin (No)
No
BAL, stool negative
Wirk & Wingard (8)
Survived
Probable pulmonary aspergillosis
Thiabendazole, ivermectin (Yes)
No
Sputum and stool
Dulley et al. (9)
Died 165 days after SS disease onset (CMV, GVHD)
No
Mebendazole, albendazole (Yes)
Yes
Urethral smear
Steiner et al. (10)
Survived
No
Ivermectin, albendazole (Yes)
No
Stool
Oberoi et al. (11)
Table 1
SS, Strongyloides stercoralis; NR, not reported; BAL, bronchoalveolar lavage; CMV, cytomegalovirus; GVHD, graft-versus-host disease.
Died (SS hyperinfection)
Outcome (cause of death)
NR
Treatment (response)
Aspergillus fumigatus and Enterobacter aerogenes pneumonia
NR
Eosinophilia after transplantation
Concomitant infections
BAL
Safdar et al. (6)
Microscopic SS documentation
Author (Reference)
Table 1 Continued
Died 15 days after SS disease onset (SS hyperinfection and septicemia)
Escherichia coli septicemia
No
No
Stool. Intestinal tissues at autopsy
Izquierdo et al. (12)
Survived
No
Albendazole (Yes)
Yes
Stool
Iori et al. (Present case)
Iori et al: Strongyloidiasis in allogeneic stem cell transplant
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Iori et al: Strongyloidiasis in allogeneic stem cell transplant
onset of strongyloidiasis, including our case, obtained rapid clearance of the infection with the addition of specific therapy and all survived (9, 11). In conclusion, strongyloidiasis is a potentially fatal complication in allo-SCT recipients. Owing to the atypical clinical presentation of the disease, the possible misdiagnosis with other frequently observed complications, and the low predictive role of the eosinophil count, strongyloidiasis is presumably underestimated in allo-SCT. The risk of underdiagnosis may be relevant in low-endemic areas, such as Europe, where immigration is a growing phenomenon. When S. stercoralis infection is suspected, previous exposure may be the only clue to guide the appropriate diagnostic and treatment approach.
Acknowledgements: Author contribution: A.P.I. and C.G. designed the research and wrote the paper; G.C., V.T., and S.G. performed the parasitological studies; A.F., S.P., and E.S. analyzed the data; and all the authors contributed to the final version of the paper. Competing interests: The authors have no competing interests.
References 1. Siddiqui AA, Berk SL. Diagnosis of Strongyloides stercoralis infection. Clin Infect Dis 2001; 33: 1040–1047. 2. Keiser PB, Nutman TB. Strongyloides stercoralis in the immunocompromised population. Clin Microbiol Rev 2004; 17: 208–217. 3. Roxby AC, Gottlieb GS, Limaye AP. Strongyloidiasis in transplant patients. Clin Infect Dis 2009; 49: 1411–1423.
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4. Marcos LA, Terashima A, Canales M, Gotuzzo E. Update on strongyloidiasis in the immunocompromised host. Curr Infect Dis Rep 2011; 13: 35–46. 5. Allen AV. Ridley DS Further observations on the formol-ether concentration technique for faecal parasites. J Clin Pathol 1970; 23: 545–546. 6. Safdar A, Malathum K, Rodriguez SJ, Husni R, Rolston KV. Strongyloidiasis in patients at a comprehensive cancer center in the United States. Cancer 2004; 100: 1531–1536. 7. Qazilbash MH, Ueno NT, Hosing C, et al. Strongyloidiasis after unrelated nonmyeloablative allogeneic stem cell transplantation. Bone Marrow Transplant 2006; 38: 393–394. 8. Wirk B, Wingard JR. Strongyloides stercoralis hyperinfection in hematopoietic stem cell transplantation. Transpl Infect Dis 2009; 11: 143–148. 9. Dulley FL, Costa S, Cosentino R, Gamba C, Saboya R. Strongyloides stercoralis hyperinfection after allogeneic stem cell transplantation. Bone Marrow Transplant 2009; 43: 741–742. 10. Steiner B, Riebold D, Wolff D, Freund M, Reisinger EC. Strongyloides stercoralis eggs in a urethral smear after bone marrow transplantation. Clin Infect Dis 2002; 34: 1280–1281. 11. Oberoi A, Varghese SR, John MJ. Strongyloides stercoralis infection in a patient undergoing allogeneic stem cell transplantation. Indian J Pathol Microbiol 2010; 53: 895–896. 12. Izquierdo I, Briones J, Lluch R, Arqueros C, Martino R. Fatal Strongyloides hyperinfection complicating a gram-negative sepsis after allogeneic stem cell transplantation: a case report and review of the literature. Case Rep Hematol 2013; 2013: 860976. 13. CDC, IDSA, ASBMT. Guidelines for preventing opportunistic infections among hematopoietic stem cell transplant recipients: recommendations of CDC, the Infectious Disease Society of America, and the American Society of Blood and Marrow Transplantation. MMWR Morbid Mortal Wkly Rep 2000; 49: 1–125. 14. Sultana Y, Gilbert GL, Ahmed BN, Lee R. Seroepidemiology of Strongyloides stercoralis in Dhaka. Bangladesh. Parasitology 2012; 139: 1513–1520. 15. Armson A, Cunningham GA, Grubb WB, Mendis AH. Murine strongyloidiasis: the effects of cyclosporin A and thiabendazole administered singly and in combination. Int J Parasitol 1995; 25: 533–535.
Transplant Infectious Disease 2014: 16: 625–630
Case report
Strongyloides stercoralis infection in allogeneic stem cell transplant: a case report and review of the literature A.P. Iori, A. Ferretti, G. Gentile, S. Gabrielli, S. Perrone, W. Barberi, G.F. Torelli, F. Natalino, E. Scalzulli, V. Totino, R. Foa, G. Cancrini, C. Girmenia. Strongyloides stercoralis infection in allogeneic stem cell transplant: a case report and review of the literature. Transpl Infect Dis 2014: 16: 625–630. All rights reserved Abstract: Strongyloides stercoralis infections may be documented in low-endemicity areas, particularly in immigrants from endemic areas. The case of a patient from Bangladesh, an immigrant to Italy who developed a S. stercoralis infection after allogeneic stem cell transplant, is described, and 7 further cases are reviewed. Because of the atypical clinical presentation, the low predictive role of the eosinophil count, and the low sensitivity of the microbiological tests, diagnosis of strongyloidiasis is a challenging problem. When a case of S. stercoralis infection is suspected, previous exposure may be the only clue to guide the diagnostic approach.
A.P. Iori1, A. Ferretti1, G. Gentile1, S. Gabrielli2, S. Perrone1, W. Barberi1, G.F. Torelli1, F. Natalino1, E. Scalzulli1, V. Totino2, R. Foa1, G. Cancrini2, C. Girmenia1 1
Dipartimento di Ematologia, Oncologia, Anatomia Patologica e Medicina Rigenerativa, Azienda Policlinico Umberto I, Sapienza University, Rome, Italy, 2Dipartimento di Sanita Pubblica e Malattie Infettive, Azienda Policlinico Umberto I, Sapienza University, Rome, Italy Key words: Strongyloides stercoralis; allogeneic stem cell transplant; immigrant; parasitological screening Correspondence to: Anna Paola Iori, Dipartimento di Ematologia, Oncologia, Anatomia Patologica e Medicina Rigenerativa, Azienda Policlinico Umberto I, Via Benevento 6, 00161 Rome, Italy Tel: 39-06-857951 Fax: 39-06-44241984 E-mail: [email protected]
Received 11 December 2013, revised 31 January 2014, accepted for publication 18 February 2014 DOI: 10.1111/tid.12239 Transpl Infect Dis 2014: 16: 625–630
Strongyloides stercoralis is a nematode, endemic in tropical and subtropical regions. Considering that it survives in small areas of low endemicity at colder temperate climates, and that it can persist for decades after the initial infection in immigrants from endemic areas, strongyloidiasis is currently considered as a possible cause of helminth infection worldwide (1). Infection occurs when the infective larvae present in the soil penetrate the naked skin, enter the blood vessels, are carried to the lungs, and migrate, via the respiratory tree, to the pharynx, completing their life cycle to adult worm in the intestinal tract (1). The parasite may cause asymptomatic infections in half of
the affected patients, or a chronic disease that can be characterized by mild pulmonary and gastrointestinal (GI) symptoms, or severe manifestations including ileus and GI bleeding. Intermittent eosinophilia can be observed and only specific serology and parasitological analyses, applied to stool specimens, duodenal content, and/or bronchoalveolar lavage fluid, can confirm the infection (1). In immunocompromised hosts, such as transplant recipients, the infective potential of the parasite is increased. Larvae may migrate through the bowel wall, travel through the venous system to the lungs, but also disseminate to every tissue of the body, in the context of continuous autoinfective internal
625
Iori et al: Strongyloidiasis in allogeneic stem cell transplant
cycles. This dissemination can produce a potentially fatal acute respiratory distress syndrome-like picture, also named hyperinfection syndrome (HS). Transplant recipients may develop S. stercoralis disease, as a progression of the chronic intestinal strongyloidiasis present before transplantation or following an allograft transmission (2–4). Here, we describe the case of a S. stercoralis infection diagnosed in a patient from Bangladesh who received an allogeneic stem cell transplant (allo-SCT) at our center in Rome. The cases reported in literature, the clinical aspects, and specific recommendations regarding prevention, diagnosis, and treatment of strongyloidiasis in allo-SCT recipients are reviewed.
Case report A 35-year-old man, born in Bangladesh where he lived until the age of 20 years, and where he returned periodically, immigrated to Italy in 1998, where he was diagnosed with acute lymphoblastic leukemia in April 2012. Six months after the achievement of complete remission with standard chemotherapy, he experienced leukemia relapse and obtained a second remission with salvage chemotherapy. In February 2013, he underwent an allo-SCT from his haploidentical brother. The pre-transplant conditioning regimen consisted of 12 Gy total body irradiation and fludarabine. Graft-versus-host disease (GVHD) prophylaxis included the standard cyclosporine, mycophenolate mofetil, and cyclophosphamide. On day +2, he developed fever and empiric piperacillin-tazobactam
plus tigecycline treatment was started. Subsequently, other antimicrobial drugs (meropenem, daptomycin, and liposomal amphotericin B) were administered because of a persistent febrile neutropenia in spite of the good clinical condition of the patient and the absence of any infectious clinical and laboratory signs. The engraftment was observed on day +17. On day +29, while remaining febrile, the patient started to present diarrhea, nausea, vomiting, asthenia, and, sporadically, generalized widespread itching. On day +37, a quick increase of eosinophils (2700/ mm3) was observed and a parasitological examination of the stools was requested. Direct smear evidenced rhabditiform non-infective larvae of S. stercoralis (Fig. 1) and Ridley concentration allowed calculation of the presence of 240 larvae/g of feces (5). Very sensitive commercial serological enzyme-linked immunosorbent assay testing applied to identify antibodies (immunoglobulin-G), specifically reacting with Strongyloides ratti somatic larval antigens (Bordier Affinity Products SA, Crissier, Switzerland), in this case proved negative. No signs or symptoms of parasitosis or peripheral blood eosinophilia had been reported in the clinical history. Parasitological stool analyses and serological investigations of his brother proved negative. Therapy with albendazole 400 mg twice a day (25 mg/kg) was started; fever disappeared after 2 days, and the patient’s clinical conditions promptly improved. After 10 days of therapy, search for the parasite was negative in 3 consecutive stool specimens. Albendazole was stopped after 20 days of treatment. The patient was discharged with complete resolution of
A
B
Fig. 1. (A) Microscopic examination of the stool sample shows at least 5 rhabditiform larvae (arrows), which measure up 380 lm long by 20 lm wide, among normal specimen debris. (B) Strongyloides stercoralis rhabditiform larva. Gray arrow indicates the packet of cells that are the genital primordium of the future adult nematode, which is fairly obvious and can be seen about two-thirds of the way back from the anterior end. The other important morphological key element to recognize this larva is the length, extremely short, of the mouth opening (only a few micrometers), clearly apparent on top of the cephalic end (black arrow).
626
Transplant Infectious Disease 2014: 16: 625–630
Iori et al: Strongyloidiasis in allogeneic stem cell transplant
the signs and symptoms previously reported, and a persistent normalization of the eosinophil count. A further search for the parasite performed after 4 months was negative.
Review of the literature and discussion A systematic review of the literature was performed by PubMed search limited to English–language articles. Including our present case, only 8 cases of strongyloidiasis in allo-SCT recipients have so far been reported to our knowledge (Table 1) (6–12). All were adult patients with hematological diseases (median age 36 years, range 33–54). The patients received their transplants in centers in America (4 patients), Europe (3 patients), and India (1 patient). All but 1 patient were from S. stercoralis-endemic areas and the remaining German patient, with an infection documented in the urinary tract, was a truck driver whose regular trucking route was between northern and southern Europe (10). Only 2 patients presented eosinophilia with clinical signs possibly related to the S. stercoralis infection before transplantation, but pre-transplant screening failed to detect the parasite; in the other 6 patients, the pre-transplant history was unremarkable. Median time for the development of signs of strongyloidiasis was 21 days after transplantation (range 2–64). The disease presented as HS in 4 cases, focal GI symptoms in 3, and urinary tract localization in 1; only our patient developed eosinophilia. Five patients died, but the parasitic infection was considered the cause of death in 3 cases (all with HS). The 3 patients who survived (including a patient with HS) were all receiving cyclosporine as GVHD prophylaxis. Strongyloidiasis is an uncommon disease in allo-SCT patients, but it is associated with a poor prognosis, especially when it evolves into a HS (6, 8, 12). Strongyloides species immunoglobulin-G enzyme-linked immunosorbent assay testing is recommended for patients from endemic areas or for patients with GI symptoms or eosinophilia before the transplant (13). Serological testing of strongyloidiasis is quite reliable and widely used, but negative results may be expected in immunocompromised subjects. Stool screening is recommended when serological testing is unavailable, or when serological findings are negative in patients with significant symptoms, eosinophilia, or a history of exposure, especially in immunocompromised patients who can have false-negative tests. At least 3 consecutive stool examinations should be performed, in view of the higher sensitivity (70%) compared with that of a single
stool examination (30%) (1). Finally, polymerase chain reaction-based techniques can be applied at some research laboratories to improve the diagnostic sensitivity. A major problem in the pre-transplant screening for S. stercoralis is represented by the frequent lack or low specificity of the clinical manifestations of infection including eosinophilia, which can be transitory or absent. Furthermore, considering that S. stercoralis can persist in the human host for decades after the initial infection, the data of earlier transitory signs suggestive for a parasitic infection can escape the pretransplant clinical history. While parasitological screening is a standard in transplant centers located in endemic areas, it may not be performed in lowendemicity areas, where knowledge of the clinical and epidemiological findings of this infection is limited. Although our patient was a native of Bangladesh, an area with a very high prevalence of S. stercoralis infections (14), we did not include a parasitological examination in the pre-transplant screening. The diagnosis of strongyloidiasis after transplantation is another challenging issue. Failure to detect larvae in a stool examination and negative immunodiagnostic assays do not necessarily indicate the unequivocal absence of the infection (1–4). Signs and symptoms of GI disease may mimic other post-transplant intestinal complications, including other infections, drug toxicity, and acute GVHD. Furthermore, intestinal acute GVHD and S. stercoralis infection may occur at the same time (7, 11). HS may be misdiagnosed or associated with other infections, and microscopic examination of the respiratory secretions may lead to an incidental recognition of S. stercoralis. With the exception of our patient, who developed a marked eosinophilia, in the other cases of S. stercoralis infection in allo-SCT recipients no abnormal eosinophil count was observed. Therefore, for post-transplant diagnosis of S. stercoralis infection, the exposure history, more than the clinical and/or laboratory findings, should guide the parasitological work-up. Our patient received albendazole treatment (the only drug immediately available at that time), with prompt disappearance of fever and of other signs and symptoms of the infection and rapid fecal clearance of the parasite. However, it should be underlined that ivermectin is the first-line therapy, as it is more effective and better tolerated than thiabendazole or albendazole for the treatment of strongyloidiasis (4). Of interest, cyclosporine may have a protective effect in S. stercoralis infection, as suggested in animal models (15). Three patients who were receiving cyclosporine as prophylaxis of GVHD concomitantly with the
Transplant Infectious Disease 2014: 16: 625–630
627
628 No
Yes, gut (21)/Yes
21
Nausea, vomiting, epigastric pain, bloating
NR
NR
NR
NR
NR
NR
NR
Pulmonary hyperinfection
Signs possibly related to SS infection before transplantation
Eosinophilia before transplantation
Screened before transplantation
Conditioning/type of donor
Cyclosporine as GVHD prophylaxis at the time of SS infection
GVHD diagnosis, site (day from allo-SCT)/steroid treatment
Timing of SS infection, days after transplantation
Clinical signs of parasitosis post transplant
Non-myeloablative/ unrelated
Yes, negative
Yes
Systemic respiratory symptoms
Idiopathic hypereosinophilic syndrome
Multiple myeloma
Underlying disease
Texas-Louisiana/ Texas
M/54
Qazilbash et al. (7)
NR/Texas
NR
Safdar et al. (6)
Site of origin of the patient/site of transplant center
Gender/age in years
Author (Reference)
Transplant Infectious Disease 2014: 16: 625–630 Abdominal pain, diarrhea
Hematuria, suprapubic pain Diarrhea, nausea, pulmonary hyperinfection
Fever, bloody diarrhea, pulmonary hyperinfection
Abdominal pain, bloody diarrhea, jaundice. Pulmonary hyperinfection
64
No/
Yes, gut (15)/Yes
15
No
Reduced intensity/NR
No
No
No
Myelodysplastic syndrome
Bolivia/Spain
M/36
Izquierdo et al. (12)
Yes
Myeloablative/sibling
No
No
No
Acute lymphoblastic leukemia
India/India
M/33
Oberoi et al. (11)
2
Yes (3 months after albendazole therapy)/NR
NR
Myeloablative/ NR
No
No
No
Chronic myeloid leukemia
Germany/ Germany
M/38
Steiner et al. (10)
54
No/Yes
Yes
Myeloablative/ sibling
No
No
No
Acute lymphoblastic leukemia
Brazil/Brazil
M/35
Dulley et al. (9)
2
No/No
No
Myeloablative/ unrelated
Yes, negative
Yes
Nausea, abdominal pain
Acute myelomonocytic leukemia
Florida/Florida
F/44
Wirk & Wingard (8)
Reported cases of strongyloidiasis in allogeneic stem cell transplant patients
Diarrhea, vomiting
29
No/No
Yes
Myeloablative/ haploidentical
No
No
No
Acute lymphoblastic leukemia
Bangladesh/ Italy
M/35
Iori et al. (Present case)
Iori et al: Strongyloidiasis in allogeneic stem cell transplant
Died 20 days after SS disease onset (multiorgan failure. At autopsy no larvae in tissues)
No
Ivermectin, Thiabendazole (No)
No
Duodenal biopsy
Qazilbash et al. (7)
Died 11 days after SS disease onset (SS hyperinfection)
Klebsiella pneumoniae and Enterococcus species septicemia
Ivermectin (No)
No
BAL, stool negative
Wirk & Wingard (8)
Survived
Probable pulmonary aspergillosis
Thiabendazole, ivermectin (Yes)
No
Sputum and stool
Dulley et al. (9)
Died 165 days after SS disease onset (CMV, GVHD)
No
Mebendazole, albendazole (Yes)
Yes
Urethral smear
Steiner et al. (10)
Survived
No
Ivermectin, albendazole (Yes)
No
Stool
Oberoi et al. (11)
Table 1
SS, Strongyloides stercoralis; NR, not reported; BAL, bronchoalveolar lavage; CMV, cytomegalovirus; GVHD, graft-versus-host disease.
Died (SS hyperinfection)
Outcome (cause of death)
NR
Treatment (response)
Aspergillus fumigatus and Enterobacter aerogenes pneumonia
NR
Eosinophilia after transplantation
Concomitant infections
BAL
Safdar et al. (6)
Microscopic SS documentation
Author (Reference)
Table 1 Continued
Died 15 days after SS disease onset (SS hyperinfection and septicemia)
Escherichia coli septicemia
No
No
Stool. Intestinal tissues at autopsy
Izquierdo et al. (12)
Survived
No
Albendazole (Yes)
Yes
Stool
Iori et al. (Present case)
Iori et al: Strongyloidiasis in allogeneic stem cell transplant
Transplant Infectious Disease 2014: 16: 625–630
629
Iori et al: Strongyloidiasis in allogeneic stem cell transplant
onset of strongyloidiasis, including our case, obtained rapid clearance of the infection with the addition of specific therapy and all survived (9, 11). In conclusion, strongyloidiasis is a potentially fatal complication in allo-SCT recipients. Owing to the atypical clinical presentation of the disease, the possible misdiagnosis with other frequently observed complications, and the low predictive role of the eosinophil count, strongyloidiasis is presumably underestimated in allo-SCT. The risk of underdiagnosis may be relevant in low-endemic areas, such as Europe, where immigration is a growing phenomenon. When S. stercoralis infection is suspected, previous exposure may be the only clue to guide the appropriate diagnostic and treatment approach.
Acknowledgements: Author contribution: A.P.I. and C.G. designed the research and wrote the paper; G.C., V.T., and S.G. performed the parasitological studies; A.F., S.P., and E.S. analyzed the data; and all the authors contributed to the final version of the paper. Competing interests: The authors have no competing interests.
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