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Clinical Infection & Immunity

Case Report

Volume 9, Number 1, March 2024, pages 25-30

Cytomegalovirus Colitis in an Immunocompetent Patient Following COVID-19

Cytomegalovirus (CMV) is a known cause of colitis in immunocompromised patients and those with inflammatory bowel disease (IBD), but it frequently causes colitis in immunocompetent patients. The first case of CMV colitis in an immunocompetent person (individual) was reported in 1988 [1]. Since then, cases have been reported in patients with chronic renal insufficiency or those undergoing hemodialysis, in addition to co-infection with bacterial gastrointestinal infections and food allergy [2]. CMV disease in the gastrointestinal (GI) tract in the general population occurs in patients with relative immunosuppression due to critical illness or comorbidities, such as diabetes mellitus, prolonged residence in the intensive care unit, autoimmune diseases, or organ failure [3, 4]. In severely ill patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection (coronavirus disease 2019 (COVID-19) disease), deep immune imbalance and depletion of T cells have been reported [5, 6]. Viruses accounted for 3% of the co-infections in a systematic review of co-infections among hospitalized patients with COVID-19 disease, with CMV being the least frequently encountered virus [7]. Subsequent infection or reactivation of CMV following a recent COVID-19 disease is a rare association. This case report details a female patient with multiple comorbidities, who developed symptoms following COVID-19 disease, and was ultimately diagnosed with CMV colitis.

A 79-year-old female with a history of coronary artery disease, heart failure with reduced ejection fraction, hypertension, diabetes mellitus type II, and a recent SARS-CoV-2 infection, was evaluated in the emergency room for nausea, vomiting, and abdominal pain. She was diagnosed with COVID-19 almost 6 weeks prior, was prescribed molnupiravir and was advised to start symptomatic management. She was seen via a telehealth visit a few days later and continued on the same treatment. She reported feeling physically weak and stated that she never returned back to normal ever since she was diagnosed with COVID-19. Vitals were stable and physical examination was unremarkable. The initial laboratory workup revealed leukocytosis. A computed tomography (CT) scan of abdomen and pelvis with intravenous (IV) contrast suggested pancolitis with dilated loops of bowels as well as stranding inflammation around the splenic flexure. The patient was treated with IV piperacillin-tazobactam for possible infectious colitis, while continuing gentle hydration and symptomatic management. She developed left lower lobe pneumonia and her antibiotics were switched to IV ceftriaxone and doxycycline. The patient continued to have symptoms and developed diarrhea and low-grade fever. A repeat CT of the abdomen and pelvis showed diffuse thickening and dilatation throughout the colon, and fecal leukocytes were positive, indicating inflammation. Additional workup for Clostridioides difficile, Giardia duodenalis, the enteric bacterial panel, and ova and parasites returned normal. Human immunodeficiency virus (HIV) test was also negative. Colonos­copy showed severe inflammation in the descending colon, congested mucosa in the transverse and ascending colon, and normal terminal ileum (Fig. 1). Biopsies were taken from the descending colon that showed ulcerated colonic mucosa with granulation and associated inflammation and scattered enlarged cells with large nucleus with nuclear and cytoplasmic inclusions. Immunohistochemistry (IHC) from biopsy specimens was also positive for CMV (Fig. 2). A polymerase chain reaction (PCR) for CMV deoxyribonucleic acid (DNA) was done which was positive. The combination of the patient’s symptoms, the findings of pancolitis and dilated loops of bowel on imaging, along with serologic and biopsy findings were consistent with colitis due to CMV infection. The patient was initially treated with IV valganciclovir and later transitioned to oral ganciclovir, which was continued upon discharge. She had a prolonged stay in the hospital. She had significant weakness during the initial part of the hospital stay, had urinary and fecal incontinence and required assistance with shifting or moving out of bed. A significant improvement was seen in her condition once antivirals were initiated, while continuing physical rehabilitation. She completed a total of 4 weeks of antiviral therapy and CMV viral load was almost undetectable at outpatient follow-up. The patient was advised to follow up outpatient at Gastroenterology and Infectious diseases clinic upon discharge.

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Figure 1. Colonoscopy. Segmental severe inflammation and congested mucosa seen in the descending colon.

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Figure 2. Colon biopsy. (a) The biopsy shows ulcerated colonic mucosa with granulation and associated inflammation. Scattered enlarged cells with large nucleus with nuclear and cytoplasmic inclusions are present. (b) CMV immunohistochemical stain is positive (arrow), confirming the diagnosis of CMV colitis. CMV: cytomegalovirus.

CMV, a double-stranded DNA virus and a member of the Herpesviridae family, also known as human herpes virus 5 (HHV 5), is ubiquitous among humans [8]. A recent systematic review estimated the global seroprevalence of CMV at 83% (95% uncertainty interval (UI): 78-88) in the general population, 86% (95% UI: 83-89) in women of childbearing age, and 86% (95% UI: 82-89) in donors of blood or organs [9]. The seroprevalence is believed to increase with age. Among adults, transmission can occur via exposure to body fluids, including tears, saliva, semen, blood or transplanted organ tissue. Close contact with young children, as well as intimate contact with adults such as kissing or sexual intercourse are the main routes of transmission. The frequency of these events and the likelihood of active viral shedding in the infected host determine success of transmission [8, 10].

The virus typically enters a latent phase and remains in the host cell for life [11]. Reactivation of the virus commonly occurs under conditions of immunosuppression, while in immunocompetent hosts, the host’s immunity controls the replication and the spread of the virus [8]. Primary and secondary mechanisms are proposed for the pathogenesis CMV colitis. In the primary mechanism, CMV proliferation in vascular endothelial cells leads to vasculitis with small vessel thrombosis and ulceration, while in the secondary mechanism, a previous underlying disease, such as IBD or ischemic colitis, destroys the colonic mucosa, leading to local immunosuppression and subsequent CMV infection [12].

CMV colitis is rare in people with adequate immunity compared to the high prevalence in immunocompromised individuals. Immunodeficiency has been reported to increase the risk of developing CMV colitis, even to a minimal extent; pregnancy, kidney failure, malignancy, and diabetes are comorbidities that are associated with developing this complication. Aging (above 55) is another condition that can increase the rate of CMV colitis [13]. The spectrum of human diseases caused by CMV is diverse and is dependent on the immune status of the host. CMV infections cause substantial morbidity and mortality in the immunocompromised host. In the immunocompetent host, the infection can be asymptomatic or present with symptoms of fever, malaise, myalgia, arthralgia, and anorexia which can mimic other conditions such as mononucleosis [14] and COVID-19 [15]. Disease in the immunocompetent hosts can manifest in a single organ or as a severe multisystem disorder; however, the latter is a rare occurrence and mainly reported in small studies and case reports [16]. CMV colitis is a frequent expression of CMV end-organ disease, and is associated with considerable morbidity, manifesting as abdominal pain, diarrhea, gastrointestinal bleeding, and colonic perforation [17].

Coinfections with pathogens, such as viruses, bacteria, and fungi, have been reported with SARS-CoV-2; however, most of the viruses are respiratory [18-22]. CMV coinfection with SARS-CoV-2 in mild COVID-19 cases in patients without serious medical conditions is very rare, and its incidence and clinical significance remain unclear [23]. Infection with CMV is reported to be associated with severity or mortality of COVID-19 [24, 25]. Reports of CMV coinfection with SARS-CoV-2 are mostly limited to severe cases, such as patients treated with systemic glucocorticoids and invasive mechanical ventilation in the intensive care unit setting [26-28]. These reports were obtained during the early phase of the COVID-19 pandemic (up to mid-2022) when the mortality rate was higher than the later phase of the pandemic (after late 2022, the Omicron phase). Although these reports [26-28] did not include data on the patients receiving vaccination against COVID-19. A rare case of SARS-CoV-2 coinfection with CMV reactivation in an immunocompromised patient after getting COVID-19 vaccination has been reported [29].

The consideration of CMV colitis is pertinent given that COVID-19, especially in severe cases, has been associated with a reduction in CD4⁺ and CD8⁺ T lymphocyte counts. Several studies indicate that the disruption of adaptive immune cells, along with an increase in the activity of T cell-mediated cytotoxicity and a general dysregulation of the immune system in COVID-19 patients [30], could potentially trigger the reactivation of CMV. Furthermore, the use of corticosteroids, a key component in the treatment regimen for COVID-19, can suppress immune function and elevate the risk of opportunistic infections or reactivation of prior CMV infection [31]. Our patient recently had COVID-19 and did not completely recover to baseline. COVID-19 notably increases the risk of gastrointestinal complications; 74-86% of them develop gastrointestinal complications. These complications range in severity and include transaminitis, mesenteric ischemia, clostridioides difficile infection and gastrointestinal bleeding [32, 33]. The patient in the current report had abdominal symptoms, imaging showed dilated loops of bowel and pancolitis, biopsy showed ulcerated mucosa and granulation, and IHC showed nuclear and cytoplasmic inclusions, along with positive PCR for CMV. These findings supported the diagnosis of CMV colitis. In the context of our patient, recent COVID-19, multiple comorbidities, physical deconditioning (and weakness) and lymphopenia were identified as the principal risk factors for the reactivation of CMV [34, 35]. It is difficult to determine if this was a reactivation of CMV due to physiologic stress from the patient’s underlying illness or it was newly acquired. In general, viral co-infections with SARS-CoV-2 are associated with increased severity of COVID-19 disease and prolonged hospital stay [36, 37]. Therefore, it is important to consider CMV colitis in the differential diagnosis for patients with recent COVID-19 presenting with nonspecific symptoms such as in our case of nausea, vomiting, and abdominal pain and the findings of pancolitis on imaging.

A significant feature of CMV colitis on endoscopic evaluation is the presence of ulcerations with a distinct, punched-out appearance, typically observed in 70-80% of patients [38]. Diagnosis of CMV disease using hematoxylin and eosin-stained tissue sections relies on detecting CMV viral inclusions, characterized by their “owl eye” appearance, which are highly specific for CMV. CMV-specific IHC is regarded as the gold standard for identifying CMV in tissue biopsies [39]. Real-time PCR for CMV DNA quantification can be used along­side endoscopy findings for diagnosis, although it only shows positive results in about 50% of patients with biopsy-confirmed CMV colitis/enteritis [40]. The CMV culture is not a desirable test due to lengthy time to obtain results which can lead to delay in care. In terms of clinical outcomes such as mortality or length of stay, randomized controlled trials of prophylaxis or treatment of CMV infection in critically ill patients have not shown benefits [41, 42]. Due to lack of concrete clinical guidelines on treatment of tissue-invasive disease in the general population, the treatment is based on the physician’s discretion to assess risks and benefits. Successful treatment with the antivirals such as ganciclovir, valganciclovir, and foscarnet has been reported in the literature for mononucleosis-like syndrome but in the absence of a controlled study [43-45]. Severe CMV disease, such as perforation or impending liver failure, certainly warrants antiviral therapy regardless of the perceived host immune status [8]. CMV colitis has excellent prognosis in general; age > 55 years, requiring surgery, male gender, and associated ulcerative colitis are predictors of poor prognosis in immunocompetent individuals [46]. The prognosis of CMV infection in patients with COVID-19 is difficult to determine due to limited literature. The reactivation of CMV in patients with severe COVID-19 has been associated with high mortality rate; however, little is known about the interactions between primary CMV and SARS-CoV-2 infections. It is unknown whether simultaneous primary CMV and SARS-CoV-2 infections are risk factors for severe COVID-19, and vice versa [47]. As further cases are reported, we will get more information on the management of CMV infection (colitis); however, we advocate for early diagnosis and treatment initiation to improve outcomes based on the currently available information.

CMV colitis, although rare in immunocompetent patients, poses diagnostic and therapeutic challenges, with early detection being crucial for improved outcomes. Our case details CMV colitis in an immunocompetent female post-COVID-19 recovery, highlighting probable immune dysregulation from either the infection or treatment, even following recovery, leading to new or reactivated CMV infection.

Acknowledgments

None to declare.

Financial Disclosure

None to declare.

Conflict of Interest

None to declare.

Informed Consent

Informed consent has been obtained.

Author Contributions

Yasir Ahmed MD: primary author, both initial and final drafting of the article, images and case description, literature review, and referencing. Umair Malik MD: initial drafting of introduction, case description and discussion. Kanza Ahmed MD: contributed to discussion, review and editing, and images. Khaleeq Siddiqui MD: description of images, final review and editing prior to publication. Fahad Malik MD: description of images, final review and editing prior to publication. Amine Hila MD: conception of the article, final review and editing prior to publication.

Data Availability

The authors declare that data supporting the findings of this study are available within the article.

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