Cytomegalovirus Infection of the Gastrointestinal Tract in Patients on Hemodialysis: A Case Report and Literature Review

TL;DR

A case report and literature review show that cytomegalovirus can cause gastrointestinal issues in hemodialysis patients, requiring early detection and treatment.

Contribution

This paper adds a new case of CMV colitis in a hemodialysis patient and reviews existing literature on the topic.

Findings

CMV infection in the GI tract was diagnosed in a hemodialysis patient through biopsy and treated successfully with valganciclovir.

A literature review identified 24 cases of CMV GI tract infections in dialysis patients, with symptoms like hematochezia and diarrhea.

Clinicians should consider CMV infection in dialysis patients with unexplained bloody diarrhea and perform endoscopy and biopsy promptly.

Abstract

Cytomegalovirus (CMV) infection is widespread in immunocompromised people, and several cases of CMV infections of the gastrointestinal (GI) tract have been reported in these individuals. We present a case of an immunocompetent patient on hemodialysis (HD) who developed CMV colitis. We also conducted a review of the literature on CMV GI tract infections among patients with chronic kidney disease undergoing dialysis. A 46-year-old man with a history of end-stage renal disease and undergoing HD developed severe diarrhea and hematochezia. A colonoscopy revealed ulcers, and CMV infection was identified in the biopsy sample. We successfully treated the patient with valganciclovir for 2 months. Our review of the literature yielded 21 articles and 24 cases of CMV GI tract infection in patients undergoing dialysis, including the current case. Hematochezia and diarrhea were purported to serve as indicators of CMV GI tract infection among patients on dialysis. Thus, clinicians should suspect CMV infection of the GI tract in dialysis patients, who experience unexplained bloody diarrhea, and promptly perform a GI endoscopy and biopsy.

Figures

Colonoscopy imagesInitial colonoscopy (upon admission) (a) reveals erosions and small well-defined ulcers (arrow), consistent with CMV colitis. The follow-up colonoscopy (b) identified scarring and a healed ulcer (arrow). Hematoxylin-eosin staining (×4, c) revealed inflammation of the colon (arrow) , and immunohistochemical staining (×10, d) detected CMV-positive intranuclear inclusions (arrow).CMV: cytomegalovirus

Flowchart of the literature review process.Three authors (T.N., I.K., and Y.O.) independently reviewed the relevant titles and abstracts in the database records, retrieved full texts for eligibility assessment, and extracted information from these cases. We performed a search using the keywords “cytomegalovirus,” “CMV,” “esophagitis,” “gastritis,” “colitis,” “enterocolitis,” “gastroenteritis,” “renal dialysis,” “hemodialysis,” “hemodialysis,” “dialysis,” “chronic,” “kidney,” “renal,” and “nephron” in the electronic databases PubMed, Embase, and Ichushi from inception until May 31, 2022. We excluded immunocompromised patients with HIV infection, recipients of solid organ or hematopoietic stem cell transplantation, those receiving immunosuppression therapy, and those who had not been treated with dialysis before CMV infection. A total of 22 articles and 24 cases of GI CMV infection among dialysis patients were included.CMV: cytomegalovirus; HIV: human immunodeficiency virus; GI: gastrointestinal

Tables

Table 1. Results of blood test on admissionALT: alanine transaminase; AST: aspartate transferase; GGTP: gamma-glutamyl transpeptidase

Test	Reference range	Results
White blood cells	4.0-10 x 103/μL	12.8
Neutrophils	40-70%	85
Lymphocytes	20-45%	9
Monocytes	5.0-12%	6
Hemoglobin	12.0-17.0 x g/dL	13.3
Hematocrit	40.0-51.0%	43.2
Platelets	150-400 x 103/μL	216
Sodium	136-146 mmol/L	134
Potassium	3.50-5.10 mmol/L	4.7
Chloride	98-106 mmol/L	99
Urea	2.5-6.6 mmol/L	29.9
Creatinine	72-127 μmol/L	744
ALT	<40 U/L	8
AST	<42 U/L	9
Bilirubin	<17 μmol/L	0.5
GGTP	7-50 U/L	33
Albumin	35-52 g/L	29
C-reactive protein	<5 mg/L	247

Table 2. A literature review on CMV enteritis in patients on hemodialysis and the case in this study [8-29]CKD: chronic kidney disease; HD: hemodialysis; PD: peritoneal dialysis; DM: diabetes mellitus; ADPKD: autosomal dominant polycystic kidney disease; HTN: hypertension; HBV: hepatitis B virus; COPD: chronic obstructive pulmonary disease; AA: Amyloid A; CABG: coronary artery bypass graft; PAF: paroxysmal atrial fibrillation; WBC: white blood cell; Ly: lymphocyte count; CRP: C-reactive protein; Hb: hemoglobin; GCV: ganciclovir; VGCV: valganciclovir.*The chief complaint is referred to as “gastrointestinal bleeding” in the paper and is interpreted as hematochezia since the colon is mentioned as the infected site.

Case No

Author

Age (years)

Sex

Type of dialysis

Dialysis vintage (months)

Underlying diseases

Chief complains

Time lag from developing symptoms to the diagnosis (days)

Diagnostic method

Infected sites

WBC (×109/L)

CRP (mg/dL)

Hb (g/dL)

Complications

Antiviral therapy (+/-)

Therapeutic duration (weeks)

Outcome

Recurrence (+/-)

1

Esforzado et al. (1993) [8]

74

Male

HD

1

DM, gastric ulcer

Hematochezia*

Biopsy

Colon

20.5 (Ly 11%)

(+: GCV)

3

Survived

2

Esforzado et al.(1993) [8]

59

Female

HD

24

DM, right food distal amputation due to peripheral vascular disease

Hematochezia, fever, abdominal pain, diarrhea

Biopsy

Colon

18.1

(+)

Survived

(-)

3

Falagas et al. (1996) [9]

57

Male

HD

6

ADPKD, HTN, nephrolithiasis, asthma, gout, HBV career

Hematochezia, abdominal pain, diarrhea

Biopsy

Colon

10.8 (Ly 7%)

11.5

Hemicolectomy

(+: GCV)

2

Survived

(-)

4

Liu et al. (2018) [10]

77

Female

HD

Type 2 DM, HTN, atrial fibrillation, congestive heart failure

Loss of appetite, nausea, epigastric pain

Biopsy

Stomach

5.3

1.9

6.2

(+: VGCV)

2

Survived

5

Kim et al. (2011) [11]

56

Male

HD

24

Type 2 DM

Watery diarrhea, abdominal pain

14

Biopsy

Colon

13.2

30

9.1

(+: GCV)

4

Survived

6

Rankin et al. (2009) [12]

72

Male

HD

COPD, type 2 DM, cardiovascular disease

Hematochezia

Biopsy

Colon

20.2

42

9.5

(+: GCV)

3

Survived

7

Sudcharoen et al. (2016) [13]

72

Male

HD

Ischemic heart disease, cerebrovascular disease, HTN, gout

Hematochezia

56

Biopsy

Colon

(+: GCV)

1

8

Tabernero et al. (2004) [14]

72

Male

HD

36

Renal tuberculosis

Fever, hematochezia, abdominal pain

21

Biopsy

Colon

2.7

9.5

(+: GCV)

3

Survived

9

Hsieh et al. (2015) [15]

59

Female

PD

60

Fever, abdominal pain

85

Biopsy

Colon

17.5

(+: GCV)

3

Survived

10

Huang et al. (2017) [16]

44

Male

HD

DM

Hematochezia, shock, abdominal pain, fever

13

Biopsy

Colon

Right-colon ischemia with pneumatosis intestinalis, hemicolectomy

(+: GCV)

12

Survived

11

Quintana et al. (2005) [17]

65

Male

PD

72

Type 2 DM, chronic neurovascular complications

Vomiting, dysphagia

29

Biopsy

Esophagitis

(+: GCV)

2

Survived

12

Lo (2017) [18]

70

Female

HD

70

Coronary artery disease

Hematemesis

Gastric fluid

Stomach

Hyperkalemia, atrial flutter

(+: GCV → VGCV)

13

Yap et al. (2016) [19]

52

Male

HD

HTN

Hematochezia, abdominal pain

Biopsy

Small intestine

5.0

(+: GCV)

14

Li et al. (2015) [20]

83

Female

HD

DM

Hematochezia

(+: GCV)

Survived

15

Isekawa et al. (2013) [21]

76

Female

HD

144

DM

Hematochezia, diarrhea

Biopsy

Colon

(+: GCV)

4

Survived

16

Imoto et al. (2010) [22]

65

Male

HD

72

Chronic nephritis, AA amyloidosis

Abdominal pain, diarrhea

Biopsy

Colon

(+: GCV)

Died

17

Okada et al. (2012) [23]

72

Female

HD

36

DM

Abdominal pain

Biopsy

Colon

16.1

9.7

15.6

Necrosis of the intestine, colectomy, colostomy

(-)

Survived

18

Asai et al.(2009) [24]

76

Male

HD

144

Chronic glomerulonephritis, CABG, PAF, cervical spondylotic myelopathy

Fever, abdominal pain, diarrhea

Biopsy

Colon

(+: GCV)

Survived

19

Bando et al. (2008) [25]

72

Male

HD

216

Renal sclerosis

Fever, abdominal pain

38

Biopsy

Colon

22

Fungal abscess of the iliopsoas muscle

(+: GCV)

Survived

20

Miyauchi et al. (2006) [26]

74

Male

HD

1

Gastric cancer, prostatic cancer, empyema, lung aspergillosis

Vomiting, hematemesis

28

Biopsy

Esophagus

15.8

7.7

3.85

(+: GCV, stopped due to pancytopenia)

Died

21

Sasaki et al. (2004) [27]

68

Female

HD

60

Tuberculosis pleurisy

Abdominal pain

84

Biopsy

Duodenum

7.1

7.9

8.7

(+: GCV)

Survived

22

Nishimoto et al. (2002) [28]

57

Female

PD

48

Cholecystectomy, acute pyelonephritis

Watery diarrhea, vomiting

Biopsy

Colon, esophagus, stomach

13.4

5.4

AA amyloidosis

(+: GCV)

5.6

Died

23

Dayasu et al. (1999) [29]

63

Male

HD

12

Hematochezia

37

Biopsy

Colon

(+: GCV)

Died

24

The present case

46

Male

HD

108

DM, shunted stenosis

Diarrhea, hematochezia

11

Biopsy

Colon

14.6

2.4

12.7

(+: VGCV)

8

Survived

(-)

Full text

Introduction

Cytomegalovirus (CMV) infection is common in immunosuppressed individuals. However, CMV reactivation can sometimes occur without immunosuppression, with blood transfusion being a risk factor for developing CMV infection among immunocompetent patients [1,2]. Although CMV can put several organ systems at risk, the gastrointestinal (GI) tract is affected most frequently in immunocompetent patients [3]. A retrospective cohort study reported that chronic kidney disease (CKD) increases the risk of CMV enteritis [4], while another revealed that even in CKD patients without the presence of overt immunodeficiency, the GI tract is the most common site of involvement [5]. Furthermore, a retrospective cohort study found that the majority of immunocompetent individuals with GI CMV disease had CKD of stage III or more and that this was significantly more common in immunocompetent rather than immunocompromised patients (62.9 vs. 24.2%, P<0.001) [6], and a literature review of 44 immunocompetent patients with CMV colitis found eight of these patients had renal failure, which was considered one of the comorbidities affecting immune function [7].

Thus, a relationship likely exists between CMV reactivation in the GI tract and CKD, particularly in the dialytic state. Here, we present a case of CMV colitis in an immunocompetent patient undergoing hemodialysis (HD) with end-stage renal disease (ESRD). We also performed a literature review and identified the characteristics of GI tract infections with CMV among patients with ESRD receiving HD or peritoneal dialysis.

Case presentation

A 46-year-old man with a 9-year history of ESRD, being treated with HD was transferred to our emergency department with complaints of diarrhea and hematochezia. One week before the transfer, he was hospitalized for 4 days with watery diarrhea. During admission, the patient was receiving levofloxacin (500 mg every 48 h) and ceftriaxone (1 g every 24 h) for the possible diagnosis of bacterial gastroenteritis. He stated he had not eaten raw poultry or eggs or traveled abroad recently, and had no history of HIV infection or blood transfusion. His ESRD was due to diabetic kidney disease. The patient was hypotensive upon admission, and a physical examination revealed tenderness in the lower middle abdomen. Laboratory tests showed elevated white blood cell (WBC) count, low hemoglobin, and elevated levels of C-reactive protein (CRP) and creatinine (Table 1). Although differential diagnosis included Campylobacter, Salmonella, and Clostridioides difficile (CD) infection, stool culture did not reveal any pathogenic bacteria, and CD toxin A/B or glutamate dehydrogenase was negative. A colonoscopy revealed erosions and small ulcers around the hepatic flexure (Figure 1a). A tissue biopsy was performed, and immunohistochemical analysis detected CMV-positive cells (Figures 1c-1d). On this basis, the patient was diagnosed with CMV colitis. There were no obvious findings on physical examination suggesting the other CMV direct effects, such as retinitis, ventriculitis, and pneumonia. We administered oral valganciclovir (VGCV, 225 mg) three times a week, and the watery diarrhea decreased. A follow-up colonoscopy was performed a month after treatment initiation. There were still multiple ulcers in the colon (Figure 1b), although the repeat biopsy was CMV-negative. Blood investigation showed normalized WBC count and CRP. He was treated with oral VGCV for 8 weeks. There were no signs of relapse at the 3-month follow-up.

Colonoscopy imagesInitial colonoscopy (upon admission) (a) reveals erosions and small well-defined ulcers (arrow), consistent with CMV colitis. The follow-up colonoscopy (b) identified scarring and a healed ulcer (arrow). Hematoxylin-eosin staining (×4, c) revealed inflammation of the colon (arrow) , and immunohistochemical staining (×10, d) detected CMV-positive intranuclear inclusions (arrow).CMV: cytomegalovirus

Discussion

We performed a literature review, the strategy for which is presented in Figure 2. The clinical characteristics of 24 patients, including our patient, are shown in Table 2 [8-29]. The median age of the patients was 68 years with 62.5% men. In 78.2% of patients, the colon was the primary infected GI site. The median period since dialysis began (dialysis vintage) was 48 months. The main symptoms of CMV gastroenterocolitis were abdominal/epigastric pain (54.1%), hematochezia (50.0%), and diarrhea (33.3%). The median time delay from symptom onset to definitive biopsy was 29 days. Of the 24 patients, one was excluded because of missing data. Twenty patients were treated with ganciclovir (GCV), two received VGCV, and one required a switch from GCV to VGCV. In one of the 20 GCV-treated patients, administration was interrupted because of pancytopenia. Regarding the prognosis, as mentioned during the follow-up period, the mortality rate was 18.1%.

Flowchart of the literature review process.Three authors (T.N., I.K., and Y.O.) independently reviewed the relevant titles and abstracts in the database records, retrieved full texts for eligibility assessment, and extracted information from these cases. We performed a search using the keywords “cytomegalovirus,” “CMV,” “esophagitis,” “gastritis,” “colitis,” “enterocolitis,” “gastroenteritis,” “renal dialysis,” “hemodialysis,” “hemodialysis,” “dialysis,” “chronic,” “kidney,” “renal,” and “nephron” in the electronic databases PubMed, Embase, and Ichushi from inception until May 31, 2022. We excluded immunocompromised patients with HIV infection, recipients of solid organ or hematopoietic stem cell transplantation, those receiving immunosuppression therapy, and those who had not been treated with dialysis before CMV infection. A total of 22 articles and 24 cases of GI CMV infection among dialysis patients were included.CMV: cytomegalovirus; HIV: human immunodeficiency virus; GI: gastrointestinal

Our study supports the hypothesis that dialysis in patients with ESRD is a risk factor for CMV infection. One case-control study did not identify renal disease requiring HD as an independent risk factor for CMV colitis in immunocompetent patients (odds ratio: 1.72, 95% CI: 0.24-12.22, P-value: 0.58) but suggested that red blood cell transfusion within 1 month of diagnosis of colitis was a risk factor [1]. This could explain why dialysis patients receiving frequent transfusions have a higher CMV infection risk. As mentioned previously, another retrospective cohort study identified CKD as a risk factor for CMV enteritis [4]. More specifically, CKD and ESRD led to dendritic cell depletion and dysfunction, reduced CD4/CD8 ratio, increased Th1/Th2 ratio, and depleted naïve and central memory CD4+ and CD8+ T cells [30]. Therefore, it remains controversial whether CMV infection of the GI tract is correlated with dialysis. Our literature review was unable to reveal the detailed history of previous blood transfusion or CD4/CD8 ratio among dialysis patients and prompts further prospective studies.

Furthermore, one retrospective cohort study on GI tract CMV disease showed that the most frequent sites of infection among 89 immunocompetent patients were the colon and rectum (66.3%), followed by the esophagus (5.6%), stomach (4.5%), and small intestine (19.1%) [6]. These results are similar to those of our review. Another literature review of CMV colitis in immunocompetent patients without chronic renal failure [31], reported that the most common presenting symptoms were fever (76%), abdominal or rectal pain (53%), hematochezia (53%), and watery diarrhea (29%). In our study, the symptoms observed in dialysis patients with CMV infection were consistent with these two studies. Additionally, our review revealed that CMV gastroenterocolitis often affects the colon and is accompanied by hematochezia or watery diarrhea. Since CMV diagnosis should be confirmed by a colon biopsy, our findings suggest that if dialysis patients present with hematochezia or watery diarrhea, a colonoscopy should be performed.

Regarding treatment, although low creatinine clearance (<20 mL/min) was reported to be a risk factor for GCV-induced thrombocytopenia [32], the cessation of GCV or VGCV treatment due to thrombocytopenia was not observed in our review, except for one patient with pancytopenia. Therefore, HD-dependent CKD may not increase the incidence of thrombocytopenia and further studies are required to evaluate adverse events associated with GCV or VGCV use in HD patients.

In our review, the median time delay from symptom onset to a definitive biopsy was 29 days, which could be attributed to several reasons. First, CMV enterocolitis is often self-limiting [33,34], and patients can be cured before being diagnosed. Second, it is uncommon for clinicians to suspect CMV infection in immunocompetent patients. Finally, clinicians may not perform a biopsy of a suspicious lesion in some cases, preventing CMV detection at an earlier stage.

A limitation of our study is that the literature review methodology can have reporting bias, lack of generalizability, and a large amount of missing data. Thus, prospective studies are required to confirm the relationship between ESRD with HD and CMV infections of the GI tract in the future.

Conclusions

To our knowledge, this is the first literature review on CMV infections of the GI tract in patients on HD. Hematochezia and diarrhea were observed as the likely symptoms that increase the pretest probability of CMV reactivation in the GI tract among HD patients. Our analysis suggests that clinicians should suspect CMV infection of the GI tract in dialysis patients, who experience unexplained bloody diarrhea, and promptly perform GI endoscopy and biopsy.