Cytomegalovirus Diseases of the Gastrointestinal Tract: History
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Subjects: Allergy
Contributor:
Puo-Hsien Le

Cytomegalovirus (CMV), a double-stranded DNA virus, is an important member of the Herpesviridae family. CMV infection can manifest as asymptomatic, constitutional symptoms or tissue-invasive diseases. The gastrointestinal (GI) tract is one of the most commonly involved systems and associated with 30% of tissue-invasive diseases among immunocompetent patients. CMV GI disease is defined on the basis of upper and/or lower GI symptoms, macroscopic mucosal lesions, and CMV documented in tissue by histopathology, virus isolation, rapid culture, immunohistochemistry (IHC), or DNA hybridization techniques. However, IHC staining has a higher sensitivity and specificity than routine HE staining.

  • cytomegalovirus
  • gastrointestinal tract
  • prognostic factor
  • antiviral therapy

1. Introduction

Emerging research has shown that CMV diseases involved both immunocompromised and immunocompetent hosts [1][2][3][4]. The whole alimentary tract can be infected, but leading sites are the colon and esophagus [5]. CMV infection can worsen the outcomes of underlying GI diseases. For example, it increases the risk of hospitalization, colectomy, and even mortality in patients with inflammatory bowel disease (IBD) [6][7].
Studies regarding CMV disease of the whole GI tract were limited either by the small sample size or heterogeneous study population. Lin et al. reported the clinical and endoscopic features of alimentary tract CMV disease seen in 20 cases [8]. In adult patients with cancer, Ko et al. noted that male sex, low body mass index, lymphopenia, hematological malignancy, steroid use, and red blood cell transfusion within a month prior to the CMV disease diagnosis were independent risk factors for the development of CMV GI disease [9]. The two latest retrospective studies that enrolled 213 and 173 patients with positive H&E or IHC staining in Thailand found that antiviral treatment was the only protective factor that improved patient survival [2][4].

2. Clinical Presentation and Diagnostic Work-Up

Initial presentations included GI bleeding (45.8%), fever (33.1%), and abdominal pain (31.5%). The small intestine group had a higher proportion of patients with these core symptoms. Some gastrointestinal symptoms, such as diarrhea, were specific to enterocolitis and were not compared.
Endoscopically, ulcer was the major feature among all the groups (Figure 1). Inflammation, without concurrent ulcer or polypoid lesions, was observed in less than 15% of the cases in each group.
Viruses 14 00352 g002 550
Figure 1. The endoscopic features of CMV diseases in different segments of the GI tract. CMV, cytomegalovirus; GI, gastrointestinal.
In laboratory examinations, patients predominately showed anemia, hypoalbuminemia, elevated CRP levels, and mildly elevated Cr levels. CMV status tests were not routinely performed for every patient, thus the results were relatively incomplete. The positive rates of CMV-IgG, CMV-IgM, antigenemia, and viremia were 97.2%, 18.3%, 54.8%, and 70.8%, respectively.

3. Treatment and Outcome

The mean duration of admission was 41.2 days. Eleven (3.1%) patients developed CMV-related GI tract perforation. Twenty-five (7%) patients required surgical treatment for CMV GI disease-associated indications, with the small intestine group accounting for almost three-fold of the average (20%).
Approximately 60% of patients received antiviral therapy, including oral (PO), intravenous (IV), or both forms sequentially (Combo). Ganciclovir was the solely utilized IV form agent, while valganciclovir and ganciclovir (four patients) were the two PO form agents documented. Only 16% of patients received Combo therapy; in this group, the minimal duration was 14 days, while the mean duration of IV form and the total duration were 14.9 ± 7.9 and 39.9 ± 25 days, respectively. Influenced by the individual’s clinical status (renal function, cytopenia, and so on), the dose and duration of antiviral therapy appeared heterogeneous and were difficult to compare and analyze.
The mean duration of follow-up was approximately 2.5 years. Fourteen cases (3.9%) of recurrence were observed in the colon group. The in-hospital mortality rate was 20.8% for the entire cohort, with the small intestine, colon, stomach, and esophagus groups ranked in descending order. The overall mortality rate was 40.4%.

4. Cytomegalovirus Diseases of the Gastrointestinal Tract

CMV diseases, regardless of the end organs, are traditionally considered an infection primarily for immunocompromised patients. However, cohort studies of the GI tract in the past decades have composed a proportion of 25–50% of immunocompetent hosts [2][4][10]. Old age, critical illness, diabetes mellitus, chronic kidney disease, end-stage renal disease, and other comorbidities can lead to immune deficiency and increase the risk of CMV diseases [10][11][12]. However, these features traditionally do not define an immunocompromised status. Clinical physicians should keep the diagnosis in mind when this high-risk group of patients present with relative symptoms.
The diagnosis of CMV GI diseases is challenging because of the diverse presentations, endoscopic findings, biopsy locations, and laboratory methods. Symptoms and laboratory parameters are not distinguishable from other etiologies of infectious diseases. Variable ulcers are the most common endoscopic features of CMV infection; however, diagnosis based on endoscopic findings is difficult [11][13][14]. Although serology tests provide a hint of CMV diseases, their results correlate inadequately to the presence and severity of CMV tissue invasion; hence, histopathology remains the gold standard to confirm the tissue invasion by CMV in an inflammatory background [15][16]. However, the percentage of CMV viremia was relatively low. In the hospital, CMV IHC staining was widely used in clinically or pathologically suspicious cases. In this way, it might identify more mild GI CMV disease without viremia. Compared to H&E staining, IHC staining provides higher sensitivity and specificity [6][17].
Once the diagnosis is confirmed, the dosage or prescription of immunosuppressive drugs and steroids could be reduced or stopped, respectively. Although the efficacy and benefit of antiviral agents for general CMV diseases in patients undergoing organ transplantation and with HIV infection have been addressed in reviews and guidelines, they are still controversial in other conditions [18][19]. Most recommendations were made for immunocompromised populations, while the evidence for immunocompetent populations was limited [2][3][10][20][21]. Two studies mentioned that anti-viral therapies improved the in-hospital survival in both immunocompetent and compromised patients with 14 and 21 day therapeutic durations [7][9]. In other review articles, they suggested antiviral treatment for at least 2–3 weeks [2][22]. In this study, we found that Combo therapy (IV + PO) (minimal duration: 2 weeks, average duration: 5 weeks) resulted in better in-hospital survival rates in both immunocompetent and immunocompromised groups. Patients who received both IV and PO anti-viral agents tended to have a more complete therapeutic course than others. Nevertheless, the patients who received only IV form of anti-viral agents had a higher mortality rate in both groups; they received only IV drugs without extended oral antiviral agents, which might be due to their critical condition. Additionally, side effects of antiviral agents, including acute kidney injury and pancytopenia, might have given rise to poorer outcomes. This was the first study to compare the survival of patients with different immune statuses and treatment courses.

This entry is adapted from the peer-reviewed paper 10.3390/v14020352

References

  1. Andrews, P.A.; Emery, V.; Newstead, C. Summary of the British Transplantation Society guidelines for the prevention and management of CMV disease after solid organ transplantation. Transplantation 2011, 92, 1181–1187.
  2. Razonable, R.R.; Humar, A. Cytomegalovirus in solid organ transplant recipients—Guidelines of the American Society of Transplantation Infectious Diseases Community of Practice. Clin. Transplant. 2019, 33, e13512.
  3. You, D.M.; Johnson, M.D. Cytomegalovirus infection and the gastrointestinal tract. Curr. Gastroenterol. Rep. 2012, 14, 334–342.
  4. Rafailidis, P.I.; Mourtzoukou, E.G.; Varbobitis, I.C.; Falagas, M.E. Severe cytomegalovirus infection in apparently immunocompetent patients: A systematic review. Virol. J. 2008, 5, 47.
  5. Azer, S.A.; Limaiem, F. Cytomegalovirus Colitis; StatPearls Publishing: Treasure Island, FL, USA, 2021.
  6. Gravito-Soares, E.; Almeida, N. Cytomegalovirus disease of the upper gastrointestinal tract: An emerging infection in immunocompetent hosts. GE-Port. J. Gastroenterol. 2017, 24, 259–261.
  7. O’Hara, K.M.; Pontrelli, G.; Kunstel, K.L. An introduction to gastrointestinal tract CMV disease. J. Am. Acad. Physician Assist. 2017, 30, 48–52.
  8. Wetwittayakhlang, P.; Rujeerapaiboon, N.; Wetwittayakhlung, P.; Sripongpun, P.; Pruphetkaew, N.; Jandee, S.; Chamroonkul, N.; Piratvisuth, T. Clinical features, endoscopic findings, and predictive factors for mortality in tissue-invasive gastrointestinal cytomegalovirus disease between immunocompetent and immunocompromised patients. Gastroenterol. Res. Pract. 2021, 2021, 8886525.
  9. Chaemsupaphan, T.; Limsrivilai, J.; Thongdee, C.; Sudcharoen, A.; Pongpaibul, A.; Pausawasdi, N.; Charatcharoenwitthaya, P. Patient characteristics, clinical manifestations, prognosis, and factors associated with gastrointestinal cytomegalovirus infection in immunocompetent patients. BMC Gastroenterol. 2020, 20, 22.
  10. Reddy, N.; Wilcox, C.M. Diagnosis & management of cytomegalovirus infections in the GI tract. Expert Rev. Gastroenterol. Hepatol. 2007, 1, 287–294.
  11. Yoon, J.; Lee, J.; Kim, D.S.; Lee, J.W.; Hong, S.W.; Hwang, H.W.; Hwang, S.W.; Park, S.H.; Yang, D.-H.; Ye, B.D.; et al. Endoscopic features and clinical outcomes of cytomegalovirus gastroenterocolitis in immunocompetent patients. Sci. Rep. 2021, 11, 6284.
  12. Bernard, S.; Germi, R.; Lupo, J.; Laverrière, M.H.; Masse, V.; Morand, P.; Gavazzi, G. Symptomatic cytomegalovirus gastrointestinal infection with positive quantitative real-time PCR findings in apparently immunocompetent patients: A case series. Clin. Microbiol. Infect. 2015, 21, 1121.e1–1121.e7.
  13. Le, P.-H.; Kuo, C.-J.; Wu, R.-C.; Hsu, J.-T.; Su, M.-Y.; Lin, C.-J.; Chiu, C.-T. Pancolitis associated with higher mortality risk of cytomegalovirus colitis in patients without inflammatory bowel disease. Ther. Clin. Risk Manag. 2018, 14, 1445–1451.
  14. Lee, J.S.; Yun, J.; Ham, S.; Park, H.; Lee, H.; Kim, J.; Byeon, J.-S.; Jung, H.-Y.; Kim, N.; Kim, D.H. Machine learning approach for differentiating cytomegalovirus esophagitis from herpes simplex virus esophagitis. Sci. Rep. 2021, 11, 3672.
  15. Ljungman, P.; Boeckh, M.; Hirsch, H.H.; Josephson, F.; Lundgren, J.; Nichols, G.; Pikis, A.; Razonable, R.R.; Miller, V.; Griffiths, P.D. Definitions of cytomegalovirus infection and disease in transplant patients for use in clinical trials. Clin. Infect. Dis. 2016, 64, 87–91.
  16. Gravito-Soares, E.; Almeida, N. Cytomegalovirus disease of the upper gastrointestinal tract: An emerging infection in immunocompetent hosts. GE-Port. J. Gastroenterol. 2017, 24, 259–261.
  17. Reddy, N.; Wilcox, C.M. Diagnosis & management of cytomegalovirus infections in the GI tract. Expert Rev. Gastroenterol. Hepatol. 2007, 1, 287–294.
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