Pseudomembranous colitis due to Cytomegalovirus infection during SARS COVID-19 convalescence

Rohan Yewale; Banumathi Ramakrishna; Naveen Chand; Balakrishnan S Ramakrishna

doi:10.4103/ghep.ghep_24_21

CASE REPORT

Year : 2021 | Volume : 1 | Issue : 4 | Page : 155-158

Pseudomembranous colitis due to Cytomegalovirus infection during SARS COVID-19 convalescence

Rohan Yewale¹, Banumathi Ramakrishna², Naveen Chand¹, Balakrishnan S Ramakrishna¹
¹ Department of Medical Gastroenterology and Hepatology, SRM Institute for Medical Science Hospital, Chennai, Tamil Nadu, India
² Department of Pathology, SRM Institute for Medical Science Hospital, Chennai, Tamil Nadu, India

Date of Submission	17-May-2021
Date of Acceptance	31-May-2021
Date of Web Publication	24-Sep-2021

Correspondence Address:
Rohan Yewale
Department of Medical Gastroenterology and Hepatology, SRM Institute for Medical Science Hospital, No. 1, Jawaharlal Nehru Salai, 100 Feet Road, Vadapalani, Chennai - 600 026, Tamil Nadu
India

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ghep.ghep_24_21

Abstract

Pseudomembranous colitis (PMC) is a well-known entity with an increasing prevalence in the current post antibiotic era. Its endoscopic and histological morphology is often considered synonymous with Clostridioides difficile-associated colitis. Cytomegalovirus (CMV) infection is a less commonly reported cause of PMC. We report an interesting case of a 61-year-old gentleman with an acute-onset, inflammatory diarrhea during SARS COVID-19 convalescence who was found to have features consistent with PMC on colonoscopy. However, histological and immunohistochemistry analysis of colonic biopsies revealed the presence of CMV infection in the absence of C. difficile toxins on stool assay.

Keywords: Clostridioides difficile, convalescence, Cytomegalovirus, diarrhea, pseudomembranous colitis, SARS COVID-19

How to cite this article:
Yewale R, Ramakrishna B, Chand N, Ramakrishna BS. Pseudomembranous colitis due to Cytomegalovirus infection during SARS COVID-19 convalescence. Gastroenterol Hepatol Endosc Pract 2021;1:155-8

How to cite this URL:
Yewale R, Ramakrishna B, Chand N, Ramakrishna BS. Pseudomembranous colitis due to Cytomegalovirus infection during SARS COVID-19 convalescence. Gastroenterol Hepatol Endosc Pract [serial online] 2021 [cited 2022 Aug 18];1:155-8. Available from: http://www.ghepjournal.com/text.asp?2021/1/4/155/326630

Introduction

Pseudomembranous colitis (PMC) is a well-known entity that has classically been used to describe Clostridioides difficile-associated colitis (CDAC).^[1],[2],[3] With rampant use of antimicrobials for a plethora of confirmed as well as suspected infections, the prevalence of C. difficile infection has markedly increased. Consistent with this epidemiological trend, the discovery of PMC on endoscopy and histology invariably leads to the diagnosis of CDAC, the morphological finding being considered synonymous with the infection. PMC is an umbrella term typically used to describe the endoscopic/histological appearance of pseudo-membranes which can occur due to a multitude of risk factors such as intestinal surgery, intestinal ischemia, and a few other enteric infections even in the absence of CDAC.^[4] A less commonly reported cause of PMC is Cytomegalovirus (CMV) colitis.^[5],[6],[7] The concomitant presence of CMV-PMC in an individual convalescing from COVID-19 infection has not previously been reported. We report an interesting case of a 61-year-old gentleman with a melange of varied entities that finds increasing relevance in the current pandemic era which has served to broaden our spectrum of differential diagnosis for every possible symptom complex encountered in day-to-day practice.

Case Report

A 61-year-old gentleman presented as an outpatient with complaints of diarrhea for 7 days. His stools were semi-solid to watery in consistency (predominantly, Bristol type 6), small volume with a frequency of 8 to 10 times per day associated with urgency and occasional episodes of fecal incontinence. He also complained of persistent lower abdominal pain which was mild to moderate in intensity and crampy in character associated with constant burning sensation in the anal region. There was no passage of blood or mucus in the stools, and he did not complain of any extra-intestinal manifestations. He was diagnosed with diabetes mellitus, systemic hypertension, and triple-vessel coronary artery disease 9 months previously and underwent coronary artery bypass graft surgery 2 months prior to this presentation. He had been hospitalized for COVID-19-related pneumonia 1 month prior to the current presentation. During that period, he required noninvasive ventilatory support for about 7 days and was administered intravenous steroid (methylprednisolone), antibiotics (azithromycin, piperacillin-tazobactam), and antiviral medication (remdesivir). He had recovered completely from COVID-19 illness and was asymptomatic apart from postviral fatigue before the onset of the present episode of diarrheal illness. General, abdominal, and rectal examination were unremarkable on presentation. Baseline laboratory investigations showed essentially normal complete blood count, renal function tests, and serum electrolytes. He was initiated on an antidiarrheal diet and administered with antispasmodic/analgesic medication on an as-needed basis. Diarrhea, lower abdominal pain, and perianal burning did not respond to conservative management. In view of the persistent abdominal pain which was out of proportion to the findings on physical examination, a computed tomography scan of the abdomen was performed, which showed diffuse thickening of the large bowel wall, with perirectal fat stranding without any evidence of small- or large-bowel ischemia. The medical gastroenterology team intervened at this point of time and a colonoscopy was planned. Colonoscopy performed up to the terminal ileum showed multiple, scattered, sub-centimetric ulcers with yellowish white exudates and normal appearance of intervening mucosa in the cecum and ascending colon [Figure 1]. In addition, large, irregular, coalescent, semi-circumferential, ulcers with slough in the base, were noted extending proximally from the anal verge up to the lower one-third of the rectum [Figure 2]. Biopsies were obtained from the ileum, cecum, and rectum, inclusive of the ulcer base and margins and sent for histopathological examination. Ileal biopsy showed a mild increase in eosinophils. Biopsy from the caecum showed mucosal ulcerations covered by a volcano-like lesion with a pseudomembrane composed of fibrin, mucin, and neutrophils [Figure 3]. Few dilated and ruptured crypts containing aggregates of neutrophils in the lumen were present beneath this lesion. In one fragment, few enlarged endothelial cells with CMV inclusion bodies, focally surrounded by neutrophils, were present [Figure 4]. Rectal biopsy showed focal superficial ulceration and mild active inflammation. No viral inclusion bodies were detected. Blood quantitative CMV polymerase chain reaction (PCR) was reported as negative. Stools for C. difficile toxin A, toxin B, and glutamate dehydrogenase assay were negative. Due to a high index of suspicion for CMV infection, the cecal biopsy paraffin block was sent for CMV immunohistochemistry (IHC) analysis, which came out to be positive. On this clinical backdrop of an acute-onset, short-duration, painful, large bowel type of diarrhea with a recent history of COVID-19 infection which demanded antimicrobial and intravenous steroid usage and present colonoscopic evidence of pseudomembranes and ulcers with histological/IHC evidence of CMV infection, a final diagnosis of CMV-induced PMC was made. The patient was treated with ganciclovir for 14 days and discharged with near-complete resolution of symptoms. On subsequent telephonic follow-up after a fortnight, he was doing well without any significant complaints.

Figure 1: Panel A, Panel B: Multiple, scattered, sub-centimetric ulcers with yellowish white exudates and normal appearance of intervening mucosa in the cecum and ascending colon. This is the endoscopic equivalent of the volcano-like lesions noted at histopathology

Click here to view

Figure 2: Large, irregular, coalescent, semi-circumferential, slough-based ulcers extending proximally from the anal verge up to the lower one-third of the rectum

Click here to view

Figure 3: Volcano-like lesion with a pseudomembrane composed of fibrin, mucin, and neutrophils. Hematoxylin and eosin,–×100

Click here to view

Figure 4: Enlarged cells with Cytomegalovirus inclusion bodies, focally surrounded by neutrophils (black arrows). Hematoxylin and eosin, ×400

Click here to view

Discussion

Pseudomembrane formation is akin to a variety of infectious, toxic, ischemic, and inflammatory processes that cause mucosal injury and ulceration of the intestine [Table 1].^[4] Although the inciting trigger for pseudomembrane formation may vary across different entities, the pathophysiology is explained by a common pathologic cascade. The postulated theories for this cascade include elaboration of luminal toxins by ingested or commensal microorganisms, circulatory failure, and poor mucosal perfusion with intravascular coagulation resulting in localized Schwartzman reaction.^[8],[9],[10] In the postantibiotic era, CDAC constitutes the prototype of pathological entities associated with pseudomembrane formation. On the other hand, most series have described colonic ulceration as the most common finding in patients with CMV colitis.^[6] A less commonly reported manifestation of CMV colitis is pseudomembrane formation.^[5],[6],[7] This clinical presentation has been reported by Wilcox et al. in just two out of 31 patients with CMV colitis (8%) in their case series.^[6] The neutrophilic inflammatory changes in CMV usually affect endothelial cells with characteristic owl-eyed nuclear or granular cytoplasmic inclusions. Mucosal vascular involvement may lead to ischemia and thereby contribute to ulceration and pseudomembrane formation. Few authors in the past have tried to histologically differentiate CDAC PMC from that associated with ischemic colitis with or without associated CMV infection. In a study of 49 pathologic specimens, Dignan and Greenson reported that hyalinized lamina propria appeared to be a very sensitive and specific marker for pseudomembranes resulting from ischemia.^[11] There have also been a few case reports in the past which have reported the co-existence of C. difficile and CMV infection causing PMC especially in inflammatory bowel disease patients on immunosuppression.^[12] SARS COVID-19 is postulated to affect the gastrointestinal tract in many possible ways including direct mucosal toxicity due to expression of ACE receptors over the gastrointestinal mucosa as well as indirect effects such as medication-related side effects, dysbiosis, and systemic inflammatory response syndrome.^{[13],[14],[15]} Of late, there have also been quite a few reports of unexplained thrombotic events during convalescence from COVID-19 infection.^[16] Our patient had a combination of risk factors which included recent antibiotic use, prolonged nosocomial exposure, steroid-induced immunosuppression, and recent COVID-19 infection. The possibility of co-colitis, that is, co-infection with CMV and C. difficile, was ruled out by the absence of C. difficile-related toxins on stool assay. Abdominal imaging ruled out any form of colonic ischemia in our case. Although blood CMV quantitative PCR came out to be negative, the classic histological appearance of enlarged endothelial cells with inclusion bodies prompted IHC analysis of colonic biopsy, which thereby confirmed the diagnosis of CMV-associated PMC. The identification of PMC at colonoscopy should not automatically be assumed as CDAC, and other conditions including CMV infection should be retained in the differential diagnosis.

Table 1: Causes of pseudomembranous colitis

Click here to view

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient has given his consent for his images and other clinical information to be reported in the journal. The patient understand that name and initials will not be published and due efforts will be made to conceal identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

References

1.	Tedesco FJ, Barton RW, Alpers DH. Clindamycin-associated colitis. A prospective study. Ann Intern Med 1974;81:429-33.
2.	Green RH. The association of viral activation with penicillin toxicity in guinea pigs and hamsters. Yale J Biol Med 1974;47:166-81.
3.	Hafiz S. Clostridium difficile and its Toxins [Dissertation]. Leeds, UK: University of Leeds; 1974.
4.	Farooq PD, Urrunaga NH, Tang DM, von Rosenvinge EC. Pseudomembranous colitis. Dis Mon. 2015;61:181-206. doi:10.1016/j.disamonth.2015.01.006.
5.	Olofinlade O, Chiang C. Cytomegalovirus infection as a cause of pseudomembrane colitis: A report of four cases. J Clin Gastroenterol 2001;32:82-4.
6.	Wilcox CM, Chalasani N, Lazenby A, Schwartz DA. Cytomegalovirus colitis in acquired immunodeficiency syndrome: A clinical and endoscopic study. Gastrointest Endosc 1998;48:39-43.
7.	Franco J, Massey BT, Komorowski R. Cytomegalovirus infection causing pseudo-membranous colitis. Am J Gastroenterol 1994;89:2246-8.
8.	Pothoulakis C, LaMont JT. Clostridium difficile colitis and diarrhea. Gastroenterol Clin North Am 1993;22:623-37.
9.	Bongaerts GP, Lyerly DM. Role of toxins A and B in the pathogenesis of Clostridium difficile disease. Microb Pathog 1994;17:1-12.
10.	Norris HT. Recent advances in ischemic bowel disease. In: Fenoglio-Preiser CM, editor. Progress in Surgical Pathology. Vol. 11. New York: WW Norton; 1990:69-77.
11.	Dignan CR, Greenson JK. Can ischemic colitis be differentiated from C difficile colitis in biopsy specimens? Am J Surg Pathol 1997;21:706-10.
12.	Chang R. Co-Colitis: A rare case of C. difficile and CMV coinfection in an IBD patient, Am J Gastroenterol 2015;110:S310.
13.	Cheung KS, Hung IF, Chan PP, Lung KC, Tso E, Liu R, et al. Gastrointestinal manifestations of SARS-CoV-2 infection and virus load in fecal samples from a Hong Kong Cohort: Systematic review and meta-ANALYSIS. Gastroenterology 2020;159:81-95.
14.	D'Ardes D, Boccatonda A, Schiavone C, Santilli F, Guagnano MT, Bucci M, et al. A Case of Coinfection with SARS-COV-2 and cytomegalovirus in the Era of COVID-19. Eur J Case Rep Intern Med 2020;7:001652. Published 2020 Apr 11.
15.	Moss P. “The ancient and the new”: Is there an interaction between cytomegalovirus and SARS-CoV-2 infection? Immun Ageing 2020;17:14.
16.	Keshavarz P, Rafiee F, Kavandi H, Goudarzi S, Heidari F, Gholamrezanezhad A. Ischemic gastrointestinal complications of COVID-19: A systematic review on imaging presentation. Clin Imaging 2021;73:86-95.