Schistosomal colitis without granuloma formation in a kidney transplant recipient
Hatim MY Mudawi*, Elwaleed AM Elhassan, Omer Z Baraka and Ahmed M El Hassan About the authors
Correspondence *Department of Internal Medicine, Faculty of Medicine, University of Khartoum, PO Box 2245, Khartoum, Sudan
Email hmudawi@hotmail.com
Summary
Background A 40-year-old male from the White Nile region in Sudan, who had received a kidney transplant 6 years previously, presented with fever, lower abdominal pain and diarrhea stained with blood of 5 months duration. He was on immunosuppressive maintenance therapy, consisting of ciclosporin 75 mg twice daily, prednisolone 10 mg once daily, and azathioprine 75 mg once daily.
Investigations Laboratory investigations, liver function tests, renal function tests, stool microscopy, stool culture, abdominal ultrasound, and colonoscopy.
Diagnosis Severe, left-sided colitis due to Schistosoma mansoni infection, without granuloma formation.
Management Oral antischistosomal therapy with praziquantel at a dose of 40 mg/kg body weight.
Keywords:
The case
A 40-year-old male, who had received a kidney transplant in 1999, presented 6 years after the transplant with a 5 month history of low-grade fever, colicky lower abdominal pain, diarrhea stained with blood (5–10 motions per day), and reported a weight loss of more than 10 kg. He was taking immunosuppressive maintenance therapy, consisting of ciclosporin 75 mg twice daily, prednisolone 10 mg once daily and azathioprine 75 mg once daily.
The patient was born in the White Nile region in Sudan, (an area endemic for intestinal schistosomiasis) but had been living in Khartoum, the capital, for the past 15 years until he moved back to his home town 3 years before his presentation to our department. He was a nonsmoker and had no family history of bowel malignancy. Metronidazole and ciprofloxacin had been given for presumed amoebic and/or bacillary dysentery on several occasions over the past 5 months, but without symptomatic improvement.
On physical examination he looked ill; he was pale and emaciated, with a temperature of 38 °C, a pulse of 100 beats/min and a blood pressure of 100/80 mmHg. Abdominal examination revealed lower abdominal tenderness without guarding or rebound tenderness. He had a surgical scar, and a palpable transplanted kidney in the left iliac fossa. Rectal examination was normal. He had no joint swellings and his skin was normal.
Laboratory investigations revealed a low hemoglobin concentration, a reduced white blood cell count (mainly neutrophils, with a normal eosinophil count), an elevated platelet count, elevated erythrocyte sedimentation rate, and elevated creatinine level (Table 1). He had normal albumin, electrolyte, calcium and phosphorus levels and liver function test results (Table 1). Stool analysis showed numerous red blood cells with some pus cells, and no trophozoites or ova. Stool culture was negative.
Table 1 Laboratory investigations of a kidney transplant recipient with schistosomal colitis.
Full tableFigures & Tables indexDownload Power Point slide (86K)
Abdominal ultrasound was normal, apart from showing the transplanted kidney in the left iliac fossa. Colonoscopy revealed an inflamed mucosa with multiple superficial ulcers and loss of vascular pattern up to the splenic flexure, indicative of severe, left-sided colitis; several biopsies were taken. The rest of the colon looked normal up to the terminal ileum. Histopathology of colonic mucosa sections showed edema of the lamina propria and several Schistosoma mansoni ova without granuloma formation (Figure 1). Some ova were viable and some had a lateral spine, typical of S. mansoni ova. There were crypt abscesses containing neutrophils and eosinophils. The lamina propria contained lymphocytes, plasma cells and few eosinophils.
Figure 1 Histology slides of the colonic mucosa of a 40-year-old kidney transplant recipient with severe, left-sided colitis due to Schistosoma mansoni infection.
(A) In the center of the field (arrow) is a viable Schistosoma mansoni egg (intact miracidial nuclei) in the lamina propria without surrounding granuloma. At the upper left of the slide is a gland lacking Goblet cells. (Hematoxylin and eosin staining, 
40). (B) The slide shows the collapsed walls of two degenerating S. mansoni eggs (fragmented miracidial nuclei) without surrounding granuloma. At the top of the slide is part of a gland (Hematoxylin and eosin staining, 40).
The patient was treated with oral antischistosomal therapy in the form of praziquantel at a dose of 40 mg/kg body weight. He showed a good response to this treatment.
Discussion of diagnosis
The life cycle of the blood fluke S. mansoni begins with the passage of eggs in the feces of infected humans. The eggs hatch in fresh water and release miracidia (free-swimming larvae), these then penetrate the tissue of the intermediate host, a species of water snail, where they multiply, and are released back to the water as cercariae, which can penetrate the skin of humans, the definitive host. Once inside the human host they transform into schistosomulae and move to the portal vein where they mature into adult worms, pair and migrate into the mesenteric veins. They might remain in the mesenteric veins for a matter of years and produce a large amount of eggs, which are released in feces or become embedded in the bowel wall. Neither dead eggs that remain indefinitely lodged in the bowel tissues nor empty egg shells left behind by miracidia (that escape into tissues) produce granuloma, but they might eventually create a foreign-body giant cell reaction.
The colonic complications of S. mansoni infection are related to the deposition of viable eggs in the terminal venules of the colonic mucosa. The descending colon is principally involved, with endoscopic features including edema, hyperemia, punctuate hemorrhage, granularity, and focal shallow ulcers; similar endoscopic features were noted in this patient. In chronic infection, there might be multiple, inflammatory pseudopolyps, largely in the rectum and sigmoid colon, which are composed of ova and marked granulomatous inflammatory reaction products. These areas also show mucosal thickening and luminal narrowing.1
Disease is caused by viable ova that contain living miracidia, which have been trapped in the tissues. The contained miracidia survive for 2–3 weeks, during which time a host cellular response is triggered, which involves the proliferation of lymphocytes, plasma cells, macrophages and eosinophils. Later, epithelioid cells appear and a granuloma is formed.
In this patient there was acute pathology but no histopathologic features of granuloma formation. In addition, eggs were not detected in his stools, probably because he had been receiving immunosuppressive therapy for the past 6 years and had contracted the infection some time during the past 3 years, after moving back to an endemic area for schistosomiasis. A study has shown that patients infected with S. mansoni who were immunosuppressed because of HIV-1 infection excreted fewer eggs than individuals who were not seropositive for HIV.2 This observation is compatible with the hypothesis that the process of excretion of schistosome eggs in the host feces requires an active host inflammatory reaction and that the efficacy of this process decreases in patients co-infected with schistosomiasis and HIV.2
An alternative explanation for the negative stool microscopy for ova in this patient is perhaps a low egg load in the tissues. Lack of granuloma formation in a renal transplant patient on immunosuppressive therapy has been previously described.3 Congenitally athymic (nude) mice exhibit marked impairment in the development of hepatic granuloma to S. mansoni eggs,4 owing to their deficient, cell-mediated, immune responses.
CBA/Ca mice rendered unresponsive to schistosome eggs by combined cyclophosphamide treatment and thymectomy showed marked reduction in granuloma formation in the liver and intestine5 and, in the early, acute stages of schistosome infection, had high mortality. The function of the granuloma is to protect the host against putative toxins secreted by miracidia, and reduced granuloma formation was associated with a reduction in egg excretion of over 90%. Tolerization of mice to S. mansoni egg antigens causes elevated type 1 and diminished type 2 cytokine responses and increased mortality in acute infection.5 Histologically, egg-tolerized mice had exacerbated hepatocyte damage, with extensive microvesicular steatosis.
Although this patient was on ciclosporin as part of his immunosuppressive therapy, it did not seem to confer any protection against schistosomiasis. Ciclosporin has some larvicidal activity against S. mansoni infection in mice,6 but there have been no reports in humans to date.
Differential diagnosis
A presentation of lower abdominal pain, fever and diarrhea stained with blood suggests either idiopathic IBD, such as ulcerative colitis, or infectious colitis. Infectious colitis in immunosuppressed patients might be caused by common pathogens such as Salmonella, Shigella, Campylobacter, Yersinia, Entamoeba histolytica and Mycobacterium tuberculosis. These agents might also infect immunocompetent individuals. Immunosuppressed patients are also prone to opportunistic infections such as cytomegalovirus, herpes simplex virus or Mycobacterium avium intracellulare.1, 7
Idiopathic colitis
Ulcerative colitis
In ulcerative colitis, inflammation is predominantly mucosal; the lamina propria becomes edematous and there is an inflammatory infiltrate of neutrophils, lymphocytes, plasma cells, macrophages and eosinophils, resulting in cryptitis and crypt abscesses. There are similarities between the clinical, endoscopic and histologic findings of this patient and patients with ulcerative colitis, including the presence of crypt abscesses, loss of mucin in the glands and the presence of eosinophils and neutrophils in the inflammatory reaction. Moreover, eosinophils are found in active ulcerative colitis, in the distal rather than the proximal colon,8 as in the case patient. The finding of S. mansoni eggs on histopathology was the most important diagnostic factor in this case. Of interest, this patient was already receiving drugs that are also used in the treatment of ulcerative colitis (prednisolone and azathioprine), which made the diagnosis of ulcerative colitis less likely.
Infectious colitis
Acute and chronic infectious diseases of the colon should always be considered in patients who present with abdominal pain and diarrhea, and who come from developing countries. The most important diagnostic tools in such cases are stool microscopy and stool culture. Endoscopy cannot usually differentiate between the different causes of colitis and, therefore, should not be the prime diagnostic tool when infectious colitis is suspected. Some of the organisms that might cause colitis include Shigella, Salmonella, Amoeba spp., and cytomegalovirus.
Shigellosis
Shigellosis is caused by a Gram-negative bacillus and intestinal damage occurs primarily by direct invasion of the organism into the colonic epithelium and, to a lesser extent, by production of bacterial enterotoxin. Shigellosis might cause severe colitis, with an endoscopic appearance very similar to ulcerative colitis; diagnosis is usually made by stool culture. The condition responds to quinolones and ampicillin.1, 7
Amebiasis
Amebiasis is caused by Entamoeba histolytica; symptomatic disease occurs when the trophozoites invade the colonic mucosa. The parasite has a predilection for the cecum and rectosigmoid area. Endoscopically, amebiasis might also mimic ulcerative colitis. Diagnosis is made by isolating the trophozoites on stool microscopy or from colonic biopsies. The disease responds to metronidazole.1, 7
Nontyphoidal salmonellosis
Nontyphoidal salmonellosis is caused by Gram-negative bacilli and can involve the small or the large intestine. It preferentially involves the right colon but might involve the whole colon; however, rectal sparing is common. The endoscopic appearance of nontyphoidal salmonellosis varies, but severe pancolitis in these patients is endoscopically similar to ulcerative colitis. Diagnosis is made by stool culture. The infection responds to quinolone treatment.1, 7
Cytomegalovirus
The pathogenesis of cytomegalovirus infection involves invasion of vascular endothelial cells, which causes vasculitis, and results in mucosal ischemic ulceration, which might present as large, isolated, punched-out ulcers. Not all individuals infected with the virus develop symptoms, but immunocompromised patients are more prone to develop symptoms than immunocompetent individuals. In renal transplant recipients, lesions are predominantly seen on the right side of the colon, and might present endoscopically with an appearance very similar to ulcerative colitis. Diagnosis is made by demonstration of the characteristic, large, viral inclusion bodies within the nucleus of infected cells. Ganciclovir, a derivative of aciclovir, is effective for treating most cases.1, 7
Treatment and management
The objective of treatment for intestinal schistosomiasis is to eradicate the trematodes, which leads to the cessation of egg laying and relief from the pathogenic effects of the eggs already present in the tissues. Praziquantel is a drug with a broad-spectrum activity against trematodes. In patients with schistosomiasis, praziquantel is given in a single dose, and functions by increasing the permeability of the membranes of the parasite cells to calcium ions. The drug induces contraction of the parasites, and results in their paralysis in the contracted state. The dying parasites are dislodged from their site of action in the host organism and either enter the systemic circulation or are destroyed by the host immune system (via phagocytosis). Other mechanisms of action of the drug include focal disintegration and disturbance of ovipositioning.9
This patient received praziquantel at a dose of 40 mg/kg body weight. His symptoms of fever, diarrhea and abdominal pain improved dramatically within 2 weeks and repeat colonoscopy at this time revealed complete healing of his colonic lesions. His renal function after treatment remained the same. Although some studies have suggested that Schistosoma-specific nephropathy might occur in the transplanted kidney,10 it was shown in a large study by Mahmoud et al.11 that Schistosoma infection had no significant impact on patient or graft outcomes, although patients were found to have a high incidence of acute and chronic ciclosporin nephrotoxicity.11
Conclusion
S. mansoni colitis should be suspected in immunosuppressed patients living in areas in which S. mansoni is endemic who present with systemic and lower gastrointestinal symptoms. The finding of S. mansoni eggs on stool analysis or on histopathology is the single most important diagnostic factor in cases of schistosomal colitis. Oral antischistosomal therapy with praziquantel has been shown to be effective for eradication of the disease.
References
- Silverstein FE and Tytgat GN (1987) Atlas of Gastrointestinal Endoscopy, edn 3 318–325 Philadelphia: W.B. Saunders Company
- Karanja DM et al. (1997) Studies on Schistosomiasis in western Kenya: 1. Evidence for immune- facilitated excretion of schistosome eggs from patients with Schistosoma mansoni and human immunodeficiency virus coinfections. Am J Trop Med Hyg 56: 515–521 | PubMed | ISI | ChemPort |
- Hillyer GV and Cangiano JL (1979) Schistosoma mansoni granuloma in immunosuppressed man. Report of a case. Trans R Soc Trop Med Hyg 73: 331–333 | Article | PubMed | ChemPort |
- Phillips SM et al. (1977) Schistosomiasis in the congenitally athymic (nude) mouse. I. Thymic dependency of eosinophilia, granuloma formation, and host morbidity. J Immunol 118: 594–599 | PubMed | ChemPort |
- Fallon PG and Dunne DW (1999) Tolerization of mice to Schistosoma mansoni egg antigens causes elevated type 1 and diminished type 2 cytokine responses and increased mortality in acute infection. J Immunol 162: 4122–4132 | PubMed | ISI | ChemPort |
- Munro GH et al. (1991) The larvicidal activity of cyclosporin A against Schistosoma mansoni in mice. Parasitology 102 (Part 1): 57–63 | PubMed | ChemPort |
- Feldman M et al. (1998) Sleisenger and Fordtran's Gastrointestinal and Liver Disease, pathophysiology, diagnosis, management, edn 6 (2 vols) 1747 Philadelphia: W.B. Saunders
- Lampinen M et al. (2005) Eosinophil granulocytes are activated during the remission phase of ulcerative colitis. Gut 54: 1714–1720 | Article | PubMed | ChemPort |
- Jernigan JA and Pearson RD (1995) Antiparasitic agents. In Principles and practice of infectious diseases, edn 4 458–492 (Eds Mandell GL et al.) New York: Churchill Livingston
- Falcao HA and Gould DB (1975) Immune complex nephropathy in schistosomiasis. Ann Intern Med 83: 148–154 | PubMed | ChemPort |
- Mahmoud KM et al. (2001) Impact of schistosomiasis on patient and graft outcome after renal transplantation: 10 years' follow-up. Nephrol Dial Transplant 16: 2214–2221 | Article | PubMed | ChemPort |
Competing interests
The authors declared no competing interests.
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Subject areas under which this article appears: Infection | Large intestine
