Saudi Journal of Kidney Diseases and Transplantation

CASE REPORT
Year
: 2013  |  Volume : 24  |  Issue : 2  |  Page : 309--314

Cytomegalovirus ischemic colitis and transverse myelitis in a renal transplant recipient


Imen Gorsane1, Sabra Aloui1, Ahmed Letaif1, Rim Hadhri2, Faouzi Haouala1, Ameur Frih1, Naceur Ben Dhia1, Mezri Elmay1, Habib Skhiri1,  
1 Department of Nephrology, Hospital Fattouma Bourguiba, Monastir, Tunisia
2 Department of Pathology, Hospital Fattouma Bourguiba, Monastir, Tunisia

Correspondence Address:
Imen Gorsane
Department of Nephrology, Hospital Fattouma Bourguiba, Monastir 5000
Tunisia

Abstract

We report a rare case of cytomegalovirus (CMV)-associated ischemic colitis and transverse myelitis (TM) occurring precociously after renal transplantation. A 57-year-old male was transplanted with a cadaveric kidney on 5 June 2009. The patient was CMV seropositive and the donor was seronegative. Transplantation was followed shortly by TM, which resulted in paraplegia. The results of magnetic resonance imaging of the spinal cord showed abnormalities. Twenty days after transplantation, he developed abdominal pain with malena and was diagnosed as having CMV-associated ischemic colitis confirmed by colonoscopy and biopsy. Serological data and identification of the viral genome by polymerase chain reaction were confirmatory for CMV. Treatment consisted of intravenous ganciclovir, followed by polyvalent immunoglobulin. The outcome was favorable. Symptomatic CMV infection is relatively common among the renal transplant population. Early colonoscopy is beneficial for making a quick diagnosis and therefore helps to institute a prompt management of CMV colitis. Myelitis is less common in transplant recipients and diagnosis, therefore, was more difficult.



How to cite this article:
Gorsane I, Aloui S, Letaif A, Hadhri R, Haouala F, Frih A, Dhia NB, Elmay M, Skhiri H. Cytomegalovirus ischemic colitis and transverse myelitis in a renal transplant recipient.Saudi J Kidney Dis Transpl 2013;24:309-314


How to cite this URL:
Gorsane I, Aloui S, Letaif A, Hadhri R, Haouala F, Frih A, Dhia NB, Elmay M, Skhiri H. Cytomegalovirus ischemic colitis and transverse myelitis in a renal transplant recipient. Saudi J Kidney Dis Transpl [serial online] 2013 [cited 2019 Dec 8 ];24:309-314
Available from: http://www.sjkdt.org/text.asp?2013/24/2/309/109588


Full Text

 Introduction



Cytomegalovirus (CMV) infections are one of the most common infectious complications among transplant recipients. CMV can cause severe disease, either via reactivation of latent CMV infection or via acquisition of primary CMV infection. Clinical syndromes of CMV infections that may be observed include colitis, pneumonitis, hepatitis, encephalitis, uveitis, retinitis, myelitis and graft rejection. CMV disease characteristically occurs after the first month post-transplant, and continues to be a significant cause of morbidity in the first six months. [1],[2]

 Case Report



A 57-year-old CMV-sero-positive man with end-stage renal failure of unknown etiology was undergoing hemodialysis since 1991. He received a CMV-sero-negative cadaveric renal transplant on 5 June 2009. Immunosuppression was by antilymphocyte globulin therapy, corticosteroids, mycophenolate mofetil (MMF) and tacrolimus. Transplantation was followed by delayed graft function due to acute tubular necrosis. Hemodialysis sessions were performed during the first 15 days. Graft function improved and serum creatinine remained stable at about 80 μmol/L 20 days after kidney transplantation.

He also developed paraplegia 24 h after transplantation, with severe bilateral leg weakness. General physical examination was unremarkable. Neurological examination showed normal cranial nerves and complete motor paralysis of both legs. Pain and light touch sensations were also reduced. Cerebrospinal fluid (CSF) and nerve conduction velocity studies were not performed. Lumbar spine magnetic resonance imaging (MRI) showed lumbar canal stenosis with degenerative disc disease and did not demonstrate increased intramedullary T2 signal [Figure 1]. He was treated with intensive physiotherapy only.{Figure 1}

Twenty days after transplantation, he developed abdominal pain and melena, which was clinically diagnosed as ischemic colitis. Colonoscopy showed multiple colonic ulcerations and the biopsy demonstrated characteristic CMV inclusion bodies, confirming the diagnosis of ischemic colitis due to CMV [Figure 2]. Blood investigations at this time showed a white blood cell count of 2.9/mm 3 , hemoglobin 7 g/dL, platelet count 120000/mm 3 , glutamic oxaloacetic transaminase (GOT) 14 U/L (normal range: 0-37 U/L), glutamic pyruvic transaminase (GPT) 6 U/L (normal: 0-40), alkaline phosphatase (AP) 82 U/L (normal range: 39-117) and lactate dehydrogenase (LDH) 247 U/L (normal: 240-480).{Figure 2}

IgG anti-CMV antibodies were elevated. CMV pp65 antigen was not performed, but CMV quantification by real-time polymerase chain reaction (PCR) showed the presence of 3.2 log 10 copies/mL (1430 copies/mL). The diagnosis of CMV infection with ischemic colitis was certain, and the associated CMV myelitis was also thought to be probably due to this etiology.

Initially, the patient was treated with intravenous (IV) infusions of gancyclovir 5 mg/kg twice a day for 21 days. The response was favorable; the serum levels of white blood cells and platelet count returned to normal within ten days. The colonic ulcers disappeared dramatically two weeks later, but the neurologic signs persisted.

Subsequently, he was given intravenous human immunoglobulin (IVIg) infusions 0.5 g/kg/day three days a week for three weeks. He started having a slow steady clinical improvement in the mobility of both legs, first observed in the distal and later in the proximal muscles. Further clinical improvement was evidenced by his ability to walk with a cane. But, bladder function did not return to normal and urinary retention was still present. MRI of the spinal cord at three months did not show any abnormalities.

 Discussion



CMV infections are one of the most common (60-70%) infectious complications among transplant recipients. [1] Symptomatic CMV infections include a heterogenous group of clinical features and laboratory findings, ranging from mild infection to severe disease. [2] CMV disease typically occurs one to four months (median: 35 days) after solid organ transplantation. The natural history of CMV disease associated with solid organ transplantation has been modified as a result of the increasing use of potent immunosuppressants and antiviral prophylaxis. [3] MM is useful for preventing acute graft rejection, it have also shown an increase in CMV infections and/or diseases. [4],[5]

Manifestations of CMV infection among immunocompromised hosts or transplant recipients have been extensively reported in the literature. CMV infections can affect almost every system. In a decreasing order of frequency, the gastrointestinal tract (colitis), the central nervous system (meningitis, encephalitis, myelitis, nerve palsies, myeloradiculopathy), hematological manifestations (hemolytic anemia and thrombocytopenia), the eye (uveitis, retinitis), liver (hepatitis), lung (pneumonitis) and thrombosis of the arterial and venous systems (deep venous thrombosis, portal vein thrombosis, pulmonary embolism). [1],[2],[3],[4],[5],[6] Several studies reported that CMV infection and disease are associated with clinical acute and chronic rejection in kidney allograft recipients. [7]

The gastrointestinal (GI) tract may be affected anywhere from the mouth to the anus. GI involvement occurs in 10-30% of organ transplant recipients; the esophagus and colon are the most commonly affected. However, in immunocompetent patients, the most frequent gastrointestinal site of CMV disease affliction was the colon and rectum. [1],[2],[3],[4],[5],[6] Symptoms including abdominal pain, anorexia, malaise, nausea, vomiting, diarrhea, and bleeding were also noted. [1]

The interval, sometimes long, between transplant and appearance of such intestinal disorders indicates the need of colonoscopy. Early and rapid examination of the GI tract may lead to discovery of the characteristic appearance of CMV colitis, enabling early aquisition of histopathologic samples from suspected areas. [1] Characteristic CMV inclusions were present mainly in stromal and endothelial cells rather than in macrophages. [6]

In kidney transplant recipients, CMV colitis may present in mild and non-specific clinical situations, or may be severe enough to require a colectomy. The recurrence of episodes of colitis raises the problem of chronic CMV infection and the question of how long treatment should be continued. [1],[2],[3],[4],[5],[6],[7],[8] As MMF can also cause adverse digestive effects, the frequency of colitis due to CMV infection may be underestimated. [9]

Colo-cutaneous fistula due to CMV is unusual. It can occur following a colonic perforation, which is rare in transplant recipients in contrast to HIV patients. [10] Only few cases of colonic perforations by cytomegalic inclusion disease were reported in transplant recipients. Although fever and abdominal pain are present in most of these patients, the immunosuppressive treatment can easily hide the clinical presentation; therefore, a patient with an intestinal perforation may commonly have only minimal clinical signs, which are non-specific. Colonic perforation, although uncommon (about 1% of cases), is potentially a fatal complication among these patients. [11]

CMV infections usually complicate the course of inflammatory bowel disease, inducing relapses, refractory ulcerative colitis or failed response to immunosuppressive therapy. [12] Concomitant infection with other pathogens such as Clostridium difficile with similar clinical manifestations may mask the diagnosis. In our patient, CMV colitis appeared 20 days after transplantation. There is no inflammatory bowel disease before the transplantation and the tests for Clostridium difficile toxin were negative.

CMV infection of the central nervous system (CNS) occurs most commonly in patients with severe immunosuppression, such as those with advanced HIV infection (i.e., AIDS) or those who have undergone bone marrow or solid organ transplantation. The infection of the CNS may affect the brain (diffuse encephalitis, ventriculo-encephalitis, cerebral mass lesions) or the spinal cord (transverse myelitis, poly-radiculomyelitis). CMV-induced transverse myelitis is characterised by subacute onset of leg weakness and numbness, progressing to flaccid paraparesis or paraplegia. Sensory loss is present but the proprioception is usually preserved. Bladder dysfunction is common with urinary retention. Concomitant retinitis is common and often subclinical. Specific cerebrospinal fluid findings are present. Laboratory studies commonly show an increased number of neutrophils in the CSF and hypoglycorrhachia. The most specific diagnostic tool is the detection of CMV DNA by PCR in the CSF. [13] Electromyography and nerve conduction studies can support the diagnosis. Imaging studies may be most useful to exclude other spinal lesions. [14] There is typically a local enlargement of the spinal cord and increased signal T2 intensity.

The interval between transplant and appearance of CNS disorders in our patient was very short. MRI was inconclusive. It remains unclear whether the neuronal damage is immune mediated or due to a cytotoxic effect of viral infection. [15] The diagnosis of CMV-associated disease is based on laboratory and/or pathologic confirmation and observation of clinical resolution after initiation of therapy. [1]

The diagnosis of CMV infection requires at least one of the following laboratory methods: serology, direct detection of CMV pp65 antigen in blood (2/100,000 cells) or CMV culture, but they are not completely sensitive and may not detect the virus despite disease progression. Biopsy, positive specific immune-histochemical staining and molecular diagnostic methods such as PCR assay appear to be more sensitive than serological or virus isolation tests; indeed, they are also more rapid. [6] To diagnose CMV infection, it is also possible to perform the identification of CMV inclusion bodies or the confocal microscopy of the eyes (to detect the "owl's eye" morphology in the corneal endothelium) or in situ hybridization.

Serological studies indicating an acute CMV infection include the presence of positive IgM anti-CMV antibodies or a significant increase in the level of IgG anti-CMV antibodies in paired samples obtained during the infection. [6],[7],[8],[9],[10],[11] Precise and linear measurements of CMV DNA load and kinetics in blood are required for optimal monitoring of both pre-emptive strategies and treatment monitoring after solid organ transplantation. The combination of automated DNA extraction and real-time PCR assay can improve CMV DNA monitoring in transplanted patients and offers advantages in terms of dynamic range and workload. [16]

It was recently shown that an ultrasensitive method based on the standard Cobas Amplicor CMV assay (Cobas CMV, Roche Molecular, Indianapolis, IN, USA) could detect 1.3 log 10 CMV DNA copies/mL (20 copies/mL) in plasma and was appropriate for the monitoring of CMV infection or reactivation both in hematopoietic stem cells and solid organ recipients. However, this method, real-time PCR assay, is time-consuming as it requires a high-speed pre-centrifugation step prior to manual extraction and has a limited linear range of 3 log 10 copies/mL. [16] In our patient, there was an increase in the level of IgG anti-CMV antibodies. CMV pp65 antigen was not performed, but real-time PCR detected 3.2 log 10 copies/ mL (1430 copies/mL).

CMV infection has been a substantial cause of mortality and morbidity among transplant recipients; however, the prognosis of the disease has changed dramatically since the introduction of ganciclovir, valganciclovir and foscarnet. [17] The risk of severe primary infection during the first 3 months after a transplant in the CMV D+/R- group is so high that a prophylaxis therapy is generally administered in most transplant centers. [11]

Once the diagnosis of CMV infection or disease is made, therapy with ganciclovir is currently the standard treatment (5 mg/kg intravenously twice a day for 21 days), but it is probably not effective for severe CMV disease like pneumonia or GI involvement, where the addition of polyvalent IVIg may be beneficial, although this is still controversial. [18] In this case, IVIg was indicated for the neurological signs that persisted with ganciclovir.

Valganciclovir, a valylester prodrug of oral ganciclovir, has recently been proposed as an alternative to IV ganciclovir for the therapy of CMV reactivation due to its higher bioavailability, which provides a drug exposure comparable to that achieved with IV ganciclovir. [19]

Adverse-effects associated with the administration of antiviral treatment against CMV ganciclovir and valganciclovir can cause myelotoxicity, CNS disorders, hepatotoxicity, ireversible infertility (inhibition of spermatogenesis) or teratogenesis. Treatment with foscarnet can cause disturbances in mineral and electrolyte homeostasis, as well as nephrotoxicity. Additionally, long-term administration of these agents may lead to the emergence of resistant viral strains. [6]

CMV continues to be, potentially, the most important pathogen affecting organ transplant recipients. Early and rapid colonoscopy is beneficial for the early diagnosis and management of CMV colitis in transplant recipients. Diagnosis of CMV myelitis is very difficult and should be based on clinical presentation, results of imaging and virological markers. The most specific diagnostic tool is the detection of CMV DNA by PCR in the CSF. These strategies for an early recognition of the disease will help improve both patient and graft survival.

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