Haemorrhagic Campylobacter jejuni and CMV colitis in a renal transplant recipient

Nigel Toussaint1, David Goodman1, Robyn Langham1,2, Hilton Gock1 and Prue Hill3

1 Department of Nephrology, 2 University of Melbourne, Department of Medicine and 3 Department of Anatomical Pathology, St. Vincent's Hospital, Melbourne, Australia

Correspondence and offprint requests to: Dr Nigel Toussaint, Department of Nephrology, St. Vincent's Hospital, PO Box 2900, Fitzroy, Victoria 3065, Australia. Email: Nigel.Toussaint{at}mh.org.au

Keywords: Campylobacter infections; colitis; cytomegalovirus infections; kidney transplantation



   Introduction
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 Introduction
 Case
 Discussion
 References
 
Cytomegalovirus (CMV) infection is a significant cause of morbidity and mortality in recipients of all organ transplants. The reported incidence of CMV infection and disease is varied, the wide range related to differences in methods of detection and in immunosuppression protocols. Nonetheless, evidence of active CMV disease can be found in up to two-thirds of patients following renal transplantation [1].

CMV infection can involve a number of organs, including the gastrointestinal tract (GIT), with a clinical presentation of abdominal pain, diarrhoea, haematochezia and constitutional symptoms, such as fever, malaise and weight loss. The factors that predispose the colon to CMV infection are unknown [2]. The virus has a tendency to infect tissues with a high cell turnover and, therefore, CMV infection may localize to the GIT mucosa in areas of inflammation. We report a case of severe necrotizing colitis related to CMV infection in a renal transplant recipient with a recent Campylobacter jejuni infection.



   Case
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 Introduction
 Case
 Discussion
 References
 
A 46-year-old male with end-stage renal disease due to reflux nephropathy received a cadaveric renal transplant. Both donor and recipient had serological evidence of past CMV infection. As per the transplantation protocol at the time, no CMV prophylaxis was given prior to or following transplantation. Initial immunosuppressive therapy consisted of basiliximab (20 mg, two doses), cyclosporin A (4 mg/kg twice daily), mycophenolate mofetil (MMF; 1000 mg twice daily) and prednisolone (25 mg daily). The graft functioned immediately with a progressive fall in serum creatinine (sCr) to 200 µmol/l [Cockcroft–Gault glomerular filtration rate (GFR) 41 ml/min)] on day 7 and a therapeutic level of cyclosporin was achieved. His post-operative course was otherwise unremarkable and he was discharged home on day 7.

Three weeks post-transplant, he developed watery diarrhoea, with up to six bowel actions daily but no rectal bleeding. The diarrhoea was attributed to MMF therapy and the MMF dose was reduced to 750 mg twice daily. There were no leukocytes or erythrocytes on faecal microscopy; however, culture isolated C. jejuni. Due to the severity of his symptoms, he received ciprofloxacin (500 mg twice daily) for 7 days. A follow-up faecal specimen ordered 3 weeks later was negative for C. jejuni. Renal function remained stable with a sCr of 120 µmol/l (GFR 69 ml/min).

Two months following the transplant, he developed increasing lethargy. He was noted to have gradually worsening thrombocytopenia, with platelet count falling from 155 000 to 72 000/mm3, and associated lymphopenia. Over the next few days, he developed fevers and epigastric pain, and presented to the hospital emergency department.

On arrival, he was noted to have a temperature of 38°C and mild epigastric tenderness. The rest of the clinical examination was unremarkable with no evidence of rash, synovitis, pharyngitis or lymphadenopathy. Initial investigations included full blood examination, demonstrating mild anaemia (haemoglobin 9.6 g/dl) and thrombocytopenia (platelets 56 000/mm3). His white cell count was 9100/mm3 (neutrophil count 8500/mm3 and lymphocytes 300/mm3). The sCr was 140 µmol/l (GFR 59 ml/min). A chest X-ray was normal and blood cultures were negative for bacterial organisms. CMV immunoglobulin (Ig) M antibodies were negative, but CMV polymerase chain reaction (PCR) testing on both urine and serum was positive for the virus. Intravenous (IV) ganciclovir was commenced at 5 mg/kg twice daily and esomeprazole 40 mg daily was introduced.

Gastroscopy the following day revealed discrete ‘target lesions’ in the stomach with necrotic centres predominantly in the antrum. Some had a ‘volcano-like’ appearance, typical of viral lesions, and there was also associated duodenitis. The gastric biopsy showed mild chronic inflammation and viral inclusions within endothelial, stromal and epithelial cells. Immunohistochemistry confirmed the presence of CMV in the intranuclear and intracytoplasmic inclusions.

Four days after treatment for CMV infection, he had improved symptomatically. His platelet count had increased to 109 000/mm3 and his sCr was 100 µmol/l. However, on the fifth day, he developed profuse diarrhoea. A faecal specimen demonstrated C. jejuni on culture. Within hours he developed GIT haemorrhage, with the passage of approximately 1000 ml of frank blood. He remained normotensive and had intravenous fluid resuscitation. A rigid sigmoidoscopy revealed proctitis and confluent inflamed sigmoid mucosa. Histology of the sigmoid mucosa showed severe colitis with occasional ‘owl eye’ CMV inclusions present in stromal cells. Viral PCR was positive for CMV DNA and the samples also cultured C. jejuni. Computed tomography of the abdomen demonstrated pan-colitis with gross colonic bowel wall thickening and relative sparing of the sigmoid colon and rectum.

The colonic bleeding continued and abdominal distension became more prominent. Meropenum (IV) was started and he was transferred to the intensive care unit (ICU) for peri-operative management. Rectal and nasogastric tubes were inserted and three units of packed cells were transfused. With increasing metabolic acidosis he underwent emergency laparotomy, which demonstrated extensive haemorrhagic necrotizing colitis involving the right hemi-colon to sigmoid. A subtotal colectomy with end ileostomy was performed.

The macroscopic pathology revealed the entire large bowel was abnormal with extensive mucosal ulceration and areas of transmural haemorrhagic infarction. Histologically, CMV inclusions were numerous within mucosal endothelial and epithelial cells. In the submucosa and serosa, there was extensive evidence of CMV vasculitis involving small veins with superimposed luminal thrombus (Figure 1A). Within the mesentery and lymph nodes, there was also evidence of CMV inclusions within endothelial cells. The segment of small bowel excised (100 mm in length) showed some mucosal endothelial CMV inclusions but no evidence of a CMV vasculitis (Figure 1B).



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Fig. 1. Large bowel. (A) A submucosal vein shows CMV vasculitis with superimposed luminal thrombus (arrow). Note that the adjacent artery on the left appears normal. Haemotoxylin and eosin; magnification: x100. (B) Within the mucosa, numerous capillary endothelial cells show nuclear and cytoplasmic CMV inclusions (arrows). Haemotoxylin and eosin; magnification: x200.

 
Post-operative recovery was unremarkable. He was discharged from ICU 2 days after surgery. IV hydrocortisone was used while the oral immunosuppression was withheld before oral prednisolone and cyclosporin were reintroduced. Azathioprine was substituted for MMF. IV ganciclovir (5 mg/kg twice daily) was continued for a further week and changed to oral valganciclovir (900 mg twice daily) for another week to complete a full 3 week course. Renal function remained stable throughout with sCr 110 µmol/l (GFR 75 ml/min). Oral valaciclovir (2 g four times a day) was commenced on discharge to continue for 3 months.



   Discussion
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 Introduction
 Case
 Discussion
 References
 
CMV is the most common infectious complication of organ transplantation and recipients commonly reactivate CMV between 1 and 4 months post-transplantation, similar to the patient in this case. In the immunocompromised, there is an imbalance between the virus and the immune system that may lead to uncontrolled viral replication. In these patients reactivation rather than reinfection or primary infection is considered the major cause of disease.

Peripheral leukocytes are thought to be the site of virus latency, but the precise mechanisms and sites of CMV latency are not understood completely, with the heart, kidney and gut all suggested as alternative sites. The most frequently infected cell types of CMV disease include endothelial cells, epithelial cells, macrophages and fibroblasts. Infection of both epithelial cells and fibroblasts results in destruction of the infected cell, possibly leading to the development of ulcerations in tissues, such as the intestine [3].

GIT CMV is thought by some to be a non-pathogenic bystander or secondary invader [2]; the presence of the virus in areas of inflammation reflecting the propensity of CMV to infect rapidly growing tissues. There is, however, strong evidence that CMV is a true gut pathogen. It is often detected in the absence of other pathogens, the severity of mucosal lesions reflects the number of CMV-infected cells and antiviral therapy benefits patients with histologically confirmed disease. In this case, the previous C. jejuni infection brought about a degree of mucosal inflammation that led to a severe episode of CMV infection in a patient who had previous exposure to CMV infection. CMV infection appears to have a specific tropism for vascular endothelium [4]. This vascular invasion may lead to a local vasculitis with subsequent damage to tissue supplied by the affected vessels.

In the GIT, CMV-affected swollen endothelial cells are thought to occlude capillary lumens and lead to an ischaemic process. Foucar et al. [5] reported a series of six renal transplant patients with severe CMV infection with colonic ulceration and lower GIT bleeding. All patients died of complications of the GIT infection, despite four having colonic resections. It is of interest that the vasculitis appears to affect small veins rather than arteries and, if severe, causes venous infarction of the large bowel, as seen in this case. Muldoon et al. [6] also reported ischaemic colitis secondary to venous thrombosis, as a result of CMV vasculitis involving large veins of the gut in a renal transplant recipient.

The mechanisms mediating CMV infection in colonic mucosa in transplant recipients are not clear. It has been suggested that CMV colitis occurs as a secondary event in gut already damaged by some other agent [2]. In this case study, the coexistent C. jejuni infection may have predisposed to CMV or exacerbated damage to the colon caused by CMV. Campylobacter jejuni has not previously been described in context with CMV colitis, but we hypothesize the potential role of C. jejuni infection and proinflammatory cytokines in CMV reactivation. There is evidence to suggest that cytokines, such as tumour necrosis factor, are involved in mechanisms of CMV reactivation [7,8].

Campylobacter infections in the non-immunosuppressed host are usually self-limiting and do not require antibiotic therapy. In a small proportion of patients who have invasive disease or are immunocompromised, treatment is needed. There has been a recent trend with the rapid emergence of antimicrobial-resistant Campylobacter strains, coinciding with the use of antibiotics in animals accelerating this trend [9]. In our patient, the C. jejuni infection may have developed resistance to the initial antibiotics administered.

In addition to C. jejuni infection, MMF therapy may have contributed to the development of severe CMV infection. Clinically important CMV colitis, primarily due to vasculitis, has increased in transplant patients treated with the triple drug immunosuppression of cyclosporin, prednisolone and MMF. It has been proposed that treatment with MMF impairs the immunoglobulin response to CMV infection and this may explain the negative assays for CMV IgM antibodies in this case study [10]. A similar case of CMV colitis has been reported involving a patient treated with mycophenolate for Wegener's granulomatosis and having a previous Salmonella infection that may also have predisposed to CMV reactivation [11].

Our case study describes a severe case of CMV infection involving a tissue-invasive vasculitis of the colon. We hypothesize that the severity of disease, despite an initial 5 days of appropriate treatment, was related to a pre-existing bacterial infection and associated pro-inflammatory cytokine release with colonic mucosal damage and possible reduced CMV antibody production following MMF therapy.

Conflict of interest statement. None declared.



   References
 Top
 Introduction
 Case
 Discussion
 References
 

  1. Brennan DC, Singer GG. Infectious complications in renal transplantation. In: Malluche HH, ed. Clinical Nephrology Dialysis and Transplantation. Landshut:Lexington 1999; 1–24
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  8. De Silva DG, Mendis LN, Sheron N et al. Concentrations of interleukin-6 and tumour necrosis factor-{alpha} by human monocytes and mucosal macrophages. J Clin Invest 1992; 90: 1642–1648[ISI][Medline]
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  10. Smak-Gregoor PJH, van Gelder T, Abraham Tanis A, Chadha-Ajwani S, Klaassen RJL, Weimar W. Cytomegalovirus colitis in a CMV seropositive renal transplant recipient on triple drug therapy (including mycophenolate). Nephrol Dial Transplant 1997; 12: 2766–2767[Abstract]
  11. Woywodt A, Choi M, Schneider W, Kettritz R, Göbel U. Cytomegalovirus colitis during mycophenolate mofetil therapy for Wegener's granulomatosis. Am J Nephrol 2000; 20: 468–472[CrossRef][ISI][Medline]
Received for publication: 18.11.04
Accepted in revised form: 13.12.04





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