Disseminated Cryptosporidium infection results in manifestations similar to those of graft‐versus‐host disease (GVHD), which hampers the detection of Cryptosporidium infection after allogeneic hematopoietic stem cell transplantation. Surveillance of oocysts on the surface of intestinal epithelial cells is needed for early and appropriate detection of Cryptosporidium infection in transplant recipients on immunosuppressants with severe intractable diarrhea. We present the first case of Cryptosporidium meleagridis infection in Japan after allogeneic cord blood transplantation

Abe, Masahiro

Fujii, Shiro

Fujino, Hikaru

Iwasa, Masami

Kagawa, Kumiko

Maruhashi, Tomoko

Miki, Hirokazu

Nakamura, Shingen

Sogabe, Kimiko

Takahashi, Mamiko

Udaka, Kengo

English

Tokushima University Institutional Repository

Transpl Infect Dis. 2018;20:e12826.	 wileyonlinelibrary.com/journal/tid	 | 	1 of 3https://doi.org/10.1111/tid.128261  | CASE REPORTA 63- year- old female in second complete remission from T- cell lym-phoblastic lymphoma was referred to our hospital for umbilical cord blood transplantation. She was treated with a non- myeloablative con-ditioning regimen consisting of intravenous infusion (iv) of 30 mg/m2 fludarabine for 6 days and 40 mg/m2 melphalan for 2 days, followed by 2 Gy total body irradiation for 2 days. A continuous iv of tacroli-mus (Tac) and 2000 mg/day oral mycophenolate mofetil (MMF) were initiated as GVHD prophylaxis. On day 18 after transplantation, her neutrophil count recovered, and she developed a mild skin erup-tion and watery diarrhea of >1000 mL/day. No bacterial, mycotic, or Clostridium difficile toxin A were detected in the stools. On day 20, we performed a colonoscopy, which indicated mild colitis. The biopsy of the edematous lesions revealed epithelial apoptosis with infiltration of inflammatory cells, which is consistent with acute gut GVHD. There were no findings of cytomegalovirus colitis. Based on the diagnosis of acute GVHD, 1 mg/kg/day prednisolone (PSL) was initiated in ad-dition to Tac and MMF. Because her diarrhea worsened, 250 mg/day methylprednisolone for 3 days was added to her regimen. However, the watery diarrhea still persisted. Intestinal biopsies were repeated on day 39, based on which acute GVHD was again diagnosed. We then treated the patient with 0.5 mg/kg/day anti- thymocyte globulin on days 47, 49, and 62. Despite these treatments, her diarrhea be-came worse similar to that which occurs in cholera, and she devel-oped vomiting with increased plasma levels of bilirubin. The laboratory data on day 82 were as follows: total bilirubin 3.6 mg/dL, aspartate aminotransferase 109 U/L, alanine aminotransferase 127 U/L, and γ- glutamyl transpeptidase 563 U/L.1.1 | Diagnosis and treatmentThe colonoscopy on day 82 indicated mild colitis with mucosal ero-sion, which we observed on day 20, and edema of the Bauhin valve  Received:	30	May	2017  |  Revised:	11	October	2017  |  Accepted:	22	October	2017DOI: 10.1111/tid.12826I M A G E S  I N  T R A N S P L A N T  I N F E C T I O U S  D I S E A S ECryptosporidiosis in a transplant recipient with severe intractable diarrhea: Detection of Cryptosporidium oocysts by intestinal biopsiesKumiko Kagawa1  | Hikaru Fujino1 | Hirokazu Miki2 | Kimiko Sogabe1 |  Mamiko Takahashi1 | Tomoko Maruhashi1 | Kengo Udaka1 | Masami Iwasa1 |  Shiro Fujii1 | Shingen Nakamura1 | Masahiro Abe11Department of Hematology, Endocrinology and Metabolism, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan2Division of Transfusion Medicine and Cell Therapy, Tokushima University Hospital, Tokushima, JapanCorrespondenceKumiko Kagawa, Department of Hematology, Endocrinology and Metabolism, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan.Email: kkag@tokushima-u.ac.jpAbstractDisseminated Cryptosporidium infection results in manifestations similar to those of graft-versus-host disease (GVHD), which hampers the detection of Cryptosporidium infection after allogeneic hematopoietic stem cell transplantation. Surveillance of oo-cysts on the surface of intestinal epithelial cells is needed for early and appropriate detection of Cryptosporidium infection in transplant recipients on immunosuppres-sants with severe intractable diarrhea. We present the first case of Cryptosporidium meleagridis infection in Japan after allogeneic cord blood transplantation.K E Y W O R D Scord blood transplantation, Cryptosporidiosis, Cryptosporidium meleagridis, graft-versus-host disease, T-cell lymphoblastic lymphomaThis is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.© 2017 The Authors. Transplant Infectious Disease Published by John Wiley & Sons Ltd2 of 3  |     KAGAWA et Al.was observed (Figure 1a and b). Biopsies of the Bauhin valve demon-strated findings consistent with mucosal apoptosis and inflammation as observed in acute GVHD; however, small spherical particles were densely aligned along the luminal surface of the epithelial cells, and Cryptosporidium oocysts were suspected (Figure 2a and b). Reevaluation of the biopsies obtained on days 39 and 68 also revealed the presence of the same organism, but not on day 20. The same organism was also noted on the surface of the duodenal epithelial cells. Stool sam-ples were positive for Cryptosporidium based on a direct fluorescent- antibody assay. A genotype analysis was performed for the surveillance of infectious disease and confirmed infection with Cryptosporidium me-leagridis. We finally diagnosed the patient as having cryptosporidiosis.We initiated anti- parasitic therapy with 500 mg/day oral azith-romycin and 1500 mg/day paromomycin and tapered PSL and MMF to restore her immune function. Her symptoms gradually improved 3 months after the initiation of anti- parasitic therapy. We performed a colonoscopy to assess the presence of oocysts and GVHD. The in-testinal biopsies demonstrated slight mucosal inflammation without oocysts nor GVHD.Her lymphocyte counts in complete blood counts decreased be-cause of the chemotherapy and prolonged immunosuppressive ther-apy. The cluster of differentiation (CD) 4- positive cell counts before and 3 months after HSCT were 50 × 106/L and 9 × 106/L respec-tively. The CD4- positive cells slightly recovered after the tapering of the immunosuppressive therapy to be 48 × 106/L 7 months after HSCT.(a)(b)F I G U R E  1   (a, b) Endoscopic appearances of the large intestine and Bauhin valve. A colonoscopy was performed on day 82. Mild erosion was widely observed on the mucosa in the colon. (a) The fold of the ascending colon. A small aphtha in the erosive fold (arrows ⇒). (b)	The	Bauhin	valve	was	edematous	(arrows	→)(a)(b)F I G U R E  2   (a, b) Histopathology of the colon biopsy. A colonoscopy was performed on day 82. Biopsy samples were obtained from the edematous lesions in the Bauhin valve as shown in Figure 1b. Hematoxylin and eosin staining. Original magnification was 100×. Bar indicates 10 μm. (a) Small spherical parasite forms were distributed along the luminal surface of epithelial cells (arrows →).	Apoptotic	bodies	in	the	crypt	epithelium,	which	are	characteristic	of GVHD, were observed (arrow ⇒). (b) The images present different details from the same biopsy. Small spherical particles on the epithelial	surface	(arrows	→)     |  3 of 3KAGAWA et Al.2  | DISCUSSIONCryptosporidium spp. can contaminate natural water sources and infect epithelial cells in the digestive tract of vertebrates through contami-nated food and water. There are over 20 genotypes of Cryptosporidium spp., and Cryptosporidium hominis and Cryptosporidium parvum repre-sent the most common species that infect humans. Cryptosporidium meleagridis typically infects birds but occasionally infects immuno-compromised hosts.Although Cryptosporidium infection causes self- limited diarrhea in immunocompetent hosts and is prevalent in developing countries, it causes life- threatening diarrhea in immunocompromised hosts.1-7 There are a few reports of mass infection of Cryptosporidium in Japan, but cryptosporidiosis in allo- HSCT has not been reported in Japan, based on a literature search. A few disseminated cryptosporidiosis cases have been reported in hospitalized post allo- HSCT patients during treatment of acute GVHD, similar to our patient.8-10 In these cases, Cryptosporidium was suggested to infect patients latently before hospitalization and disseminate systemically after extensive immuno-suppressive therapy. The prevalence of cryptosporidiosis after allo- HSCT has been prospectively studied in a single center in France.11 In this study, investigators identified Cryptosporidium parvum in 5 of the 52 patients who presented with diarrhea at a median of 503 days (range 20- 790) after allo- HSCT. The patients without cryptosporidio-sis exhibited significantly higher CD4- positive cell counts compared with those with cryptosporidiosis (median 496 × 106/L, range: 40- 3400 × 106/L and median 60 × 106/L, range: 0- 234 × 106/L respec-tively). This report suggests that cryptosporidiosis is not an extremely rare comorbidity in allo- HSCT, even in developed countries.As we experienced with our patient, cryptosporidiosis after HSCT is occasionally difficult to diagnose at an early time point and may be overlooked because of overlapping symptoms and its similarity to acute gut GVHD with respect to clinical and endoscopic manifes-tations.9,10 Although the intestinal biopsies suggested acute GVHD, the detection of oocysts residing on the intestinal mucosa led to a final diagnosis of cryptosporidiosis. Although cryptosporidiosis has not been regarded as a common cause of diarrhea after allo- HSCT in Japan, it should be considered as a comorbidity after allo- HSCT in patients on immunosuppressants with severe intractable diarrhea.CONFLICT OF INTERESTAll authors declare no conflict of interest.ORCIDKumiko Kagawa  http://orcid.org/0000-0001-6023-3293 REFERENCES 1. Hunter PR, Nichols G. Epidemiology and clinical features of Cryptosporidium infection in immunocompromised patients. Clin Microbiol Rev. 2002;15:145-154. 2. Chen XM, Keithly JS, Paya CV, LaRusso NF. Cryptosporidiosis. N Engl J Med. 2002;346:1723-1731. 3. Bhadauria D, Goel A, Kaul A, et al. Cryptosporidium infection after renal transplantation in an endemic area. Transpl Infect Dis. 2015;17:48-55. 4. Raja K, Abbas Z, Hassan SM, et al. Prevalence of cryptosporidiosis in renal transplant recipients presenting with acute diarrhea at a single center in Pakistan. J Nephropathol. 2014;3:127-131. 5. Burdese M, Veglio V, Consiglio V, et al. A dance teacher with kidney- pancreas transplant and diarrhea: What in the cause? Nephrol Dial Transplant. 2005;20:1759-1761. 6. Delis SG, Tector J, Kato T, et al. Diagnosis and treatment of Cryptosporidium infection in intestinal transplant recipients. Transplant Proc. 2002;34:951-952. 7. Franco A, Rocamora N, Merino E, Paya A. Cryptosporidosis. A rare infection in renal transplantation. Nefrologia. 2006;26:753-754. 8. Faraci M, Cappelli B, Morreale G, et al. Nitazoxanide or CD3+/CD4+ lymphocytes for recovery from severe Cryptosporidium in-fection after allogeneic bone marrow transplant? Pediatr Transplant. 2007;11:113-116. 9. Sebastián E, Martín J, McDonald GB, et al. Cryptosporidium  parvum infection vs GVHD after hematopoietic SCT: Diagnosis by PCR with resolution of symptoms. Bone Marrow Transplant. 2011;46:612-614. 10. Müller C, Zeiser R, Grüllich C, et al. Intestinal cryptosporidiosis mimicking acute graft- versus- host- disease following matched un-related hematopoietic stem cell transplantation. Transplantation. 2004;77:1478-1479. 11. Legrand F, Grenouillet F, Larosa F, et al. Diagnosis and treatment of digestive cryptosporidiosis in allogeneic haematopoietic stem cell transplant recipients: A prospective single centre study. Bone Marrow Transplant. 2011;46:858-862.How to cite this article: Kagawa K, Fujino H, Miki H, et al. Cryptosporidiosis in a transplant recipient with severe intractable diarrhea: Detection of Cryptosporidium oocysts by intestinal biopsies. Transpl Infect Dis. 2018;20:e12826.  https://doi.org/10.1111/tid.12826

Cryptosporidiosis in a transplant recipient with severe intractable diarrhea : Detection of Cryptosporidium oocysts by intestinal biopsies

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Cryptosporidiosis in a transplant recipient with severe intractable diarrhea : Detection of Cryptosporidium oocysts by intestinal biopsies

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