J Infect Chemother xxx (2014) 1e5
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Case report
Cytomegalovirus enteritis in immunocompetent subjects: A case report and review of the literature Daiki Karigane a, b, Saho Takaya b, Yuki Seki b, Yuka Mastumoto b, Akira Onose b, Arifumi Kosakai b, Norio Sugaya c, Takehiko Mori a, * a b c
Division of Hematology, Department of Medicine, Keio University School of Medicine, Tokyo, Japan Department of Internal Medicine, Keiyu Hospital, Kanagawa, Japan Department of Pediatrics, Keiyu Hospital, Kanagawa, Japan
a r t i c l e i n f o
a b s t r a c t
Article history: Received 4 September 2013 Received in revised form 25 October 2013 Accepted 1 December 2013
Cytomegalovirus (CMV) enteritis (or colitis) is generally diagnosed in immunocompromised patients in association with human immunodeficiency virus infection as well as in recipients of solid organ or hematopoietic stem cell transplant. CMV enteritis has been reported only sporadically in immunocompetent individuals. We encountered a 76-year-old woman who developed CMV enteritis without any previously identified immunocompromised states. An extensive literature review of 33 cases of CMV enteritis or colitis diagnosed in immunocompetent individuals, including the present case, revealed that the median age of the patients was 68, the accompanying symptoms were diarrhea (76%), abdominal pain (52%), and hematochezia or melena (27%), and that the outcome was generally favorable, including resolution without any treatment in 24% of the patients. CMV enteritis should be recognized more widely as a disease entity not only in immunocompromised patients but also in immunocompetent individuals, especially in elderly populations. Ó 2013, Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.
Keywords: Cytomegalovirus Enteritis Colitis Ganciclovir Immunocompetent individuals
1. Introduction Cytomegalovirus (CMV) has been well recognized as a pathogen causing opportunistic infections in immunocompromised patients [1]. After primary infection, a latent virus can reactivate under immunosuppressed states, such as stem cell or solid organ transplantation, autoimmune diseases, or acquired immunodeficiency syndrome (AIDS) [2e4]. CMV diseases following reactivation include pneumonitis, enteritis/colitis, retinitis, and hepatitis. After the introduction of sensitive monitoring of CMV reactivation, the incidence of pneumonitis decreased dramatically [3,5]. Despite such progress in the management of CMV, investigators including us have shown that CMV gastrointestinal diseases, such as enteritis and gastritis, are still clinically problematic and often impair the patient’s quality of life [6]. Although the occurrence of CMV enteritis is considered rare in immunocompetent individuals, we encountered a case of CMV enteritis without any
* Corresponding author. Division of Hematology, Department of Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan. Tel.: þ81 3 3353 1211x62385; fax: þ81 3 3353 3515. E-mail address: [email protected] (T. Mori).
immunosuppressed conditions. Since only sporadic cases of CMV enteritis have been reported in immunocompetent individuals, we here describe the clinical course of our case and review the cases in the literature. 2. Case report A 76-year-old woman complained of a 3-week history of watery diarrhea and abdominal pain. Before experiencing these gastrointestinal symptoms, she had been asymptomatic and in good condition. Her medical history included a diagnosis of pulmonary Mycobacterium avium infection, which was mild and did not require specific treatments. At her visit, she was afebrile but anemic, suffering from tenderness in the whole abdomen, and experiencing severe impairment of her daily activities. Laboratory data showed increased white blood cells (13.3 109/L), increased C-reactive protein (3.68 mg/dL), and hypoalbuminemia (serum albumin 2.4 g/ dL). Anti-human immunodeficiency virus (HIV) antibody was negative. Stool cultures for bacteria and mycobacterium were repeatedly negative. Total colonoscopy was performed, showing multiple erosions and ulcers in the terminal ileum, ileocecum, and rectum (Fig. 1). Histopathologic examination revealed diffuse ulcerative changes with lymphocyte-predominant inflammatory cell
1341-321X/$ e see front matter Ó 2013, Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.jiac.2013.12.004
Please cite this article in press as: Karigane D, et al., Cytomegalovirus enteritis in immunocompetent subjects: A case report and review of the literature, J Infect Chemother (2014), http://dx.doi.org/10.1016/j.jiac.2013.12.004
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D. Karigane et al. / J Infect Chemother xxx (2014) 1e5
Fig. 1. Endoscopic examination of the lower gastrointestinal tract. Multiple ulcers and erosive changes are observed in the terminal ileum, ileocecum, and rectum.
infiltrations and cytomegalic changes with intranuclear inclusion bodies in the mucosa and vascular endothelium, which were positive for CMV by immunohistochemical staining (Fig. 2a, b). Peripheral blood CMV antigenemia was markedly increased (246 positive cells per 50,000 neutrophils). On the basis of these findings, the diagnosis of CMV enteritis was made. Intravenous administration of ganciclovir (10 mg per kg body weight) was initiated, which improved the gastrointestinal symptoms. During the treatment with ganciclovir, the patient developed interstitial pneumonitis requiring mechanical ventilation; its etiology could not be identified even by extensive exploration for bacteria, fungi, and viruses including CMV. Treatment with glucocorticoid improved interstitial pneumonitis. However, the patient consequently succumbed due to ventilation-associated pneumonia caused by Pseudomonas aeruginosa.
3. Review of the literature on CMV enteritis/colitis We searched the English-language literature published from 1990 to 2012, using the PubMed online database. The terms cytomegalovirus colitis, enteritis, and enterocolitis were sought, and 838 reports were identified. Among these cases, we selected immunocompetent individuals aged 15 years or older with a diagnosis of CMV colitis, enteritis, or enterocolitis on the basis of
histopathological examinations of the gastrointestinal tract. In this analysis, ‘immunocompetence’ was defined as the absence of all of the following: congenital immune deficiency; HIV infection or AIDS; hematopoietic stem cell or solid organ transplantation, neoplasms, diabetes mellitus, chronic kidney disease (including treatment with hemodialysis), autoimmune disease, inflammatory bowel disease, intestinal co-infection with other microbes, systemic immunosuppressive therapy, pregnancy, and recent surgical operations. Also excluded were cases without sufficient data. Consequently, we identified 32 cases of CMV enteritis or colitis diagnosed in immunocompetent individuals who met our selection criteria. The characteristics of the 32 patients and of our present case are shown in Table 1 [7e34]. The median age at the onset of CMV colitis/enteritis was 68 years, with a range of 16e88; 25 cases (75.8%) were aged 60 years or older. Sixteen were male and 17 were female. Comorbidities were described in 7 cases: nontuberculosis mycobacterium infection (n ¼ 2), Parkinson’s disease (n ¼ 2), hyperthyroidism (n ¼ 1), bacterial pneumonia (n ¼ 1), and myocardial infarction and transient ischemic attack (n ¼ 1). The accompanying symptoms described were diarrhea (n ¼ 25: 75.8%), abdominal pain (n ¼ 17: 51.5%), hematochezia/melena/bloody stool (n ¼ 9: 27.3%) and fever (n ¼ 6: 18.2%). No specific symptoms were identified. The endoscopic findings included solitary to multiple ulcerations, mucous edema, inflamed mucosa, and minimal findings. Only 3 cases, including our case, had the descriptions of CMV antigenemia, which was positive in all 3 patients. The findings of computed tomography of the involved intestine were described in 8 cases [11,23,26,27,29e32]. The most common finding was intestinal wall thickening, and the less common were luminal dilatation and stenosis. In 8 cases (24.2%), the disease was self-limited and improved without any specific treatments. The other 25 patients received treatments for CMV colitis: 16 were treated with ganciclovir or valganciclovir, 1 with foscarnet, 3 with glucocorticoid, and 8 with surgical operation. Of the 25, 2 patients underwent combination therapy with ganciclovir and surgical operation with or without glucocorticoid. No significant differences in age or symptoms were identified between the treated and untreated groups. Regarding the outcomes, 30 patients completely recovered from CMV enteritis. Three patients died during the clinical courses because of complicated bacterial infection (n ¼ 1: present case) and post-operative infectious complications (n ¼ 2). 4. Discussion The present case, which was considered immunocompetent because there were no identifiable causes of
Fig. 2. Histological examinations of the ulcers and erosions of the ileocecal region. a) Diffuse ulcerative changes with lymphocyte-predominant inflammatory cell infiltrations and cytomegalic changes with intranuclear inclusion bodies in the mucosa and vascular endothelium were shown by by hematoxylin-eosin staining, and b) these cells were positive for CMV by immunohistochemical staining.
Please cite this article in press as: Karigane D, et al., Cytomegalovirus enteritis in immunocompetent subjects: A case report and review of the literature, J Infect Chemother (2014), http://dx.doi.org/10.1016/j.jiac.2013.12.004
D. Karigane et al. / J Infect Chemother xxx (2014) 1e5
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Table 1 Characteristics of reported cases of cytomegalovirus colitis occurring in immunocompetent individuals. Case
Age
Gender
1 2 3 4 5 6 7 8 9 10 11 12 13
35 81 36 78 68 60 68 85 67 72 67 78 79
Male Female Male Male Female Male Female Male Male Female Female Male Male
14 15 16 17 18 19 20 21 22 23 24 25
50 57 38 16 18 84 67 82 64 65 63 72
Male Female Female Female Female Female Male Male Female Female Female Female
26 27 28 29
87 88 70 72
Male Male Male Male
30 31 32 Present case
85 84 16 76 Median: 68
Male Female Female Female
Comorbidity
NTM infection
Bacterial pneumonia
Hyperthyroidism
PD PD MI, TIA
NTM infection
Symptoms
Treatment
Outcome
Reference
Diarrhea, nightsweats melena Diarrhea, hematochezia, abdominal pain Bloody diarrhea Diarrhea, abdominal pain Bloody diarrhea, abdominal pain, fever, Abdominal pain, nausea/vomiting Diarrhea, abdominal pain Diarrhea Bloody diarrhea Hematochezia, fever Bloody diarrhea Diarrhea, hematochezia, abdominal pain
Foscarnet Ganciclovir None Ganciclovir Ganciclovir None Surgical operation Ganciclovir Ganciclovir None Ganciclovir None Ganciclovir, surgical operation None None Ganciclovir Glucocorticoid Glucocorticoid Surgical operation Surgical operation Ganciclovir Ganciclovir/valganciclovir Ganciclovir None None
Recovered Recovered Recovered Recovered Recovered Recovered Recovered Died Recovered Recovered Recovered Recovered Recovered
7 8 9 10 11 12 13 14 14 15 15 16 17
Recovered Recovered Recovered Recovered Recovered Recovered Recovered Recovered Recovered Recovered Recovered Recovered
18 19 20 21 21 22 22 23 24 25 26 27
Ganciclovir Surgical operation Ganciclovir Glucocorticoid, ganciclovir, surgical operation Surgical operation Surgical operation Ganciclovir Ganciclovir
Recovered Recovered Recovered Recovered
28 29 30 31
Recovered Died Recovered Died
32 33 34 e
Diarrhea, fever, body weight loss Diarrhea, hematochezia, abdominal pain Diarrhea, fever Diarrhea Diarrhea Diarrhea, abdominal pain, fever Diarrhea, abdominal pain, fever Diarrhea, abdominal pain Diarrhea, nausea Diarrhea, nausea/vomiting Abdominal pain Diarrhea, abdominal pain, hematochezia, vomiting Diarrhea Abdominal pain Abdominal distention Diarrhea, abdominal pain Abdominal pain, vomiting Abdominal pain Diarrhea, abdominal pain, vomiting Diarrhea, abdominal pain
NTM, nontuberculous mycobacteria; PD, Parkinson disease; MI, myocardial infarction; TIA, transient ischemic attack.
immunocompromisation, presented with relatively acute-onset gastrointestinal symptoms due to CMV enteritis. Antiviral therapy with ganciclovir was initiated and improved her condition, although the patient consequently succumbed due to bacterial infectious complication. CMV enteritis/colitis is one of the manifestations of CMV diseases, which is well recognized as an opportunistic infection in association with immunocompromised states such as AIDS, solid organ or hematopoietic stem cell transplantation, and autoimmune diseases [2e6]. In general, CMV enteritis is thought to develop rarely in immunocompetent individuals, and indeed such cases have been reported only sporadically. Therefore, our experience with the present case prompted us to review the literature on CMV enteritis diagnosed in immunocompetent individuals. Although the present case developed interstitial pneumonitis during the clinical course, suggesting the possibility of impaired immune reactions, we determined the immunocompetence based on the lack of preexisting identifiable causes of immunocompromisation. Galiatsatos et al. [35] reviewed CMV enteritis histologically diagnosed in 44 immunocompetent individuals by searching cases published between 1980 and 2003 that included the term ‘CMV colitis’. Their report was the first systematic review to focus on CMV enteritis/colitis diagnosed in immunocompetent individuals, and it provided valuable findings. Although spontaneous remission of the disease was observed in 32% of the patients, advanced age, male gender, coexisting immune-modulating diseases, and colectomy were associated with a higher mortality rate [35]. However, their study had two important limitations: 1) the term ‘CMV colitis’,
which could be used interchangeably with ‘CMV enteritis’ and ‘CMV enterocolitis’, was used to search the literature; and 2) the definition of immunocompetence included coexisting immunemodulating conditions such as renal failure, diabetes mellitus, pregnancy, and untreated nonhematological malignancy. In their study, therefore, patients were subgrouped into patients with or without such conditions, and 28 cases of CMV colitis were defined as ones with intact immune systems. In addition, 10 years had passed between the last year of their literature search and the publication of their review. Thus, we attempted to refine and update the literature review of CMV enteritis/colitis in immunocompetent individuals by changing the search period to 1990e2012 to include recently published cases, extending the search terms to ‘CMV colitis’, ‘CMV enteritis’, and ‘CMV enterocolitis’, and restricting the inclusion criteria by more widely excluding the known immune-modulating or immunosuppressed conditions. In our analysis, immune-modulating or immunosuppressed conditions included diabetes mellitus, chronic kidney diseases, autoimmune diseases, malignancies, pregnancy, and surgical operation in addition to other definite states such as AIDS and organ or hematopoietic stem cell transplantation. Consequently, 32 cases fulfilled the inclusion and exclusion criteria and could be evaluated. This small number of reported cases clearly indicated the rarity of CMV enteritis in the immunocompetent population. There was no gender predominance, in contrast to the previous review [35]. However, it was consistent with the previous review that the median age of the onset of CMV enteritis was about 70 years, and that 75% of the patients were 60
Please cite this article in press as: Karigane D, et al., Cytomegalovirus enteritis in immunocompetent subjects: A case report and review of the literature, J Infect Chemother (2014), http://dx.doi.org/10.1016/j.jiac.2013.12.004
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D. Karigane et al. / J Infect Chemother xxx (2014) 1e5
years old or older. These results strongly suggest that aging could be a risk factor for CMV enteritis in immunocompetent individuals. Evidence has accumulated to show an association between aging and impaired immune reactions [36,37]. A component of alteration in the immune system, such as a decrease in naïve CD4 þ cells or an inverted ratio of CD4/CD8 cells and CD8þ T-cell repertoire disturbances, has been designated as an immunological risk phenotype or immune risk profile (IRP), and has been associated with aging and immunosenescence [38,39]. In addition, recent investigations have shown that CMV infection could have a significant effect on these aging-related changes in the immune system [40e42]. Therefore, it is plausible that the reactivation of latently infected CMV could further impair the immune system in the elderly and accelerate the development of CMV diseases. Recently, treatment with dasatinib, which is a potent inhibitor of BCR-ABL tyrosine kinase used for BCR-ABL-positive chronic myelogenous leukemia (CML) and acute lymphoblastic leukemia, has been associated with CMV reactivation and sporadic development of CMV enteritis [43,44]. An accumulation of cases of CMV enteritis associated with dasatinib treatment is required for a further evaluation of the risk of CMV reactivation in this specific population. Since there have been only sporadically reported cases and the previous review did not mention symptoms, symptoms associated with CMV enteritis in immunocompetent individuals have yet to be systematically assessed. Therefore, in the present review, we collected all the details about the symptoms associated with CMV enteritis in each case. The commonest symptom described was diarrhea (76%), followed by abdominal pain (52%). Hematochezia, melena, or bloody stool was described in only 27% of the patients, and fever was described in only 18%. Therefore, it is considered that macroscopic bloody stool and fever are not common symptoms and no specific symptoms were identified in association with CMV enteritis developing in immunocompetent hosts. Clinical significance of CMV antigenemia assay using the peripheral blood has not been fully evaluated in the setting of CMV enteritis. We have previously reported the limited use of CMV antigenemia in the prediction and diagnosis of CMV gastroenteritis in patients undergoing hematopoietic stem cell transplantation [6]. In the present literature review, only 3 cases, including the our case, had the descriptions of CMV antigenemia, which was positive in all 3 cases [20,28]. Because of the small of number of evaluable cases, it is difficult to draw a definite conclusion. However, the significance of CMV antigenemia in CMV enteritis may differ between immunocompromised and immunocompetent subjects. The patients in our review generally responded well to treatment for CMV enteritis, and their outcomes were favorable. No death directly related to CMV enteritis was observed, although there were 3 cases of death due to infectious complications directly or indirectly associated with treatment for CMV enteritis. For a majority of the patients, the treatment was the administration of anti-CMV agents (ganciclovir, valganciclovir, and foscarnet). In addition, 8 patients underwent surgical resection of the involved intestine, and 2 of the patients, aged 84 and 85 years died of infectious complication associated with the operation. The indication of surgical operation for CMV enteritis should be determined carefully, since it develops mainly in the elderly and the outcome of treatment with anti-CMV agents is good. Surprisingly, a spontaneous resolution of CMV enteritis was observed in 24% of the patients. Because of the lack of difference in this untreated group as compared with the treated group, it is impossible to identify the patients who do not need to be treated. However, spontaneous resolution could be a prominent feature of CMV enteritis developing in immunocompetent individuals. We conclude that CMV enteritis should be recognized as a disease entity not only in immunocompromised patients but also in
immunocompetent individuals, especially in the elderly. Although its prognosis is considered favorable, an accumulation of more cases is required to further elucidate the risk factors, optimal treatment, and outcomes of CMV enteritis developing in immunocompetent individuals. References [1] Taylor GH. Cytomegalovirus. Am Fam Physician 2003;67:519e24. [2] Mori T, Kato J. Cytomegalovirus infection/disease after hematopoietic stem cell transplantation. Int J Hematol 2010;91:588e95. [3] Mori T, Okamoto S, Matsuoka S, Yajima T, Wakui M, Watanabe R, et al. Riskadapted pre-emptive therapy for cytomegalovirus disease in patients undergoing allogeneic bone marrow transplantation. Bone Marrow Transpl 2000;25:765e9. [4] Mori T, Kameda H, Ogawa H, Iizuka A, Sekiguchi N, Takei H, et al. Incidence of cytomegalovirus reactivation in patients with inflammatory connective tissue diseases who are under immunosuppressive therapy. J Rheumatol 2004;31: 1349e51. 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Case report
Cytomegalovirus enteritis in immunocompetent subjects: A case report and review of the literature Daiki Karigane a, b, Saho Takaya b, Yuki Seki b, Yuka Mastumoto b, Akira Onose b, Arifumi Kosakai b, Norio Sugaya c, Takehiko Mori a, * a b c
Division of Hematology, Department of Medicine, Keio University School of Medicine, Tokyo, Japan Department of Internal Medicine, Keiyu Hospital, Kanagawa, Japan Department of Pediatrics, Keiyu Hospital, Kanagawa, Japan
a r t i c l e i n f o
a b s t r a c t
Article history: Received 4 September 2013 Received in revised form 25 October 2013 Accepted 1 December 2013
Cytomegalovirus (CMV) enteritis (or colitis) is generally diagnosed in immunocompromised patients in association with human immunodeficiency virus infection as well as in recipients of solid organ or hematopoietic stem cell transplant. CMV enteritis has been reported only sporadically in immunocompetent individuals. We encountered a 76-year-old woman who developed CMV enteritis without any previously identified immunocompromised states. An extensive literature review of 33 cases of CMV enteritis or colitis diagnosed in immunocompetent individuals, including the present case, revealed that the median age of the patients was 68, the accompanying symptoms were diarrhea (76%), abdominal pain (52%), and hematochezia or melena (27%), and that the outcome was generally favorable, including resolution without any treatment in 24% of the patients. CMV enteritis should be recognized more widely as a disease entity not only in immunocompromised patients but also in immunocompetent individuals, especially in elderly populations. Ó 2013, Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.
Keywords: Cytomegalovirus Enteritis Colitis Ganciclovir Immunocompetent individuals
1. Introduction Cytomegalovirus (CMV) has been well recognized as a pathogen causing opportunistic infections in immunocompromised patients [1]. After primary infection, a latent virus can reactivate under immunosuppressed states, such as stem cell or solid organ transplantation, autoimmune diseases, or acquired immunodeficiency syndrome (AIDS) [2e4]. CMV diseases following reactivation include pneumonitis, enteritis/colitis, retinitis, and hepatitis. After the introduction of sensitive monitoring of CMV reactivation, the incidence of pneumonitis decreased dramatically [3,5]. Despite such progress in the management of CMV, investigators including us have shown that CMV gastrointestinal diseases, such as enteritis and gastritis, are still clinically problematic and often impair the patient’s quality of life [6]. Although the occurrence of CMV enteritis is considered rare in immunocompetent individuals, we encountered a case of CMV enteritis without any
* Corresponding author. Division of Hematology, Department of Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan. Tel.: þ81 3 3353 1211x62385; fax: þ81 3 3353 3515. E-mail address: [email protected] (T. Mori).
immunosuppressed conditions. Since only sporadic cases of CMV enteritis have been reported in immunocompetent individuals, we here describe the clinical course of our case and review the cases in the literature. 2. Case report A 76-year-old woman complained of a 3-week history of watery diarrhea and abdominal pain. Before experiencing these gastrointestinal symptoms, she had been asymptomatic and in good condition. Her medical history included a diagnosis of pulmonary Mycobacterium avium infection, which was mild and did not require specific treatments. At her visit, she was afebrile but anemic, suffering from tenderness in the whole abdomen, and experiencing severe impairment of her daily activities. Laboratory data showed increased white blood cells (13.3 109/L), increased C-reactive protein (3.68 mg/dL), and hypoalbuminemia (serum albumin 2.4 g/ dL). Anti-human immunodeficiency virus (HIV) antibody was negative. Stool cultures for bacteria and mycobacterium were repeatedly negative. Total colonoscopy was performed, showing multiple erosions and ulcers in the terminal ileum, ileocecum, and rectum (Fig. 1). Histopathologic examination revealed diffuse ulcerative changes with lymphocyte-predominant inflammatory cell
1341-321X/$ e see front matter Ó 2013, Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.jiac.2013.12.004
Please cite this article in press as: Karigane D, et al., Cytomegalovirus enteritis in immunocompetent subjects: A case report and review of the literature, J Infect Chemother (2014), http://dx.doi.org/10.1016/j.jiac.2013.12.004
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Fig. 1. Endoscopic examination of the lower gastrointestinal tract. Multiple ulcers and erosive changes are observed in the terminal ileum, ileocecum, and rectum.
infiltrations and cytomegalic changes with intranuclear inclusion bodies in the mucosa and vascular endothelium, which were positive for CMV by immunohistochemical staining (Fig. 2a, b). Peripheral blood CMV antigenemia was markedly increased (246 positive cells per 50,000 neutrophils). On the basis of these findings, the diagnosis of CMV enteritis was made. Intravenous administration of ganciclovir (10 mg per kg body weight) was initiated, which improved the gastrointestinal symptoms. During the treatment with ganciclovir, the patient developed interstitial pneumonitis requiring mechanical ventilation; its etiology could not be identified even by extensive exploration for bacteria, fungi, and viruses including CMV. Treatment with glucocorticoid improved interstitial pneumonitis. However, the patient consequently succumbed due to ventilation-associated pneumonia caused by Pseudomonas aeruginosa.
3. Review of the literature on CMV enteritis/colitis We searched the English-language literature published from 1990 to 2012, using the PubMed online database. The terms cytomegalovirus colitis, enteritis, and enterocolitis were sought, and 838 reports were identified. Among these cases, we selected immunocompetent individuals aged 15 years or older with a diagnosis of CMV colitis, enteritis, or enterocolitis on the basis of
histopathological examinations of the gastrointestinal tract. In this analysis, ‘immunocompetence’ was defined as the absence of all of the following: congenital immune deficiency; HIV infection or AIDS; hematopoietic stem cell or solid organ transplantation, neoplasms, diabetes mellitus, chronic kidney disease (including treatment with hemodialysis), autoimmune disease, inflammatory bowel disease, intestinal co-infection with other microbes, systemic immunosuppressive therapy, pregnancy, and recent surgical operations. Also excluded were cases without sufficient data. Consequently, we identified 32 cases of CMV enteritis or colitis diagnosed in immunocompetent individuals who met our selection criteria. The characteristics of the 32 patients and of our present case are shown in Table 1 [7e34]. The median age at the onset of CMV colitis/enteritis was 68 years, with a range of 16e88; 25 cases (75.8%) were aged 60 years or older. Sixteen were male and 17 were female. Comorbidities were described in 7 cases: nontuberculosis mycobacterium infection (n ¼ 2), Parkinson’s disease (n ¼ 2), hyperthyroidism (n ¼ 1), bacterial pneumonia (n ¼ 1), and myocardial infarction and transient ischemic attack (n ¼ 1). The accompanying symptoms described were diarrhea (n ¼ 25: 75.8%), abdominal pain (n ¼ 17: 51.5%), hematochezia/melena/bloody stool (n ¼ 9: 27.3%) and fever (n ¼ 6: 18.2%). No specific symptoms were identified. The endoscopic findings included solitary to multiple ulcerations, mucous edema, inflamed mucosa, and minimal findings. Only 3 cases, including our case, had the descriptions of CMV antigenemia, which was positive in all 3 patients. The findings of computed tomography of the involved intestine were described in 8 cases [11,23,26,27,29e32]. The most common finding was intestinal wall thickening, and the less common were luminal dilatation and stenosis. In 8 cases (24.2%), the disease was self-limited and improved without any specific treatments. The other 25 patients received treatments for CMV colitis: 16 were treated with ganciclovir or valganciclovir, 1 with foscarnet, 3 with glucocorticoid, and 8 with surgical operation. Of the 25, 2 patients underwent combination therapy with ganciclovir and surgical operation with or without glucocorticoid. No significant differences in age or symptoms were identified between the treated and untreated groups. Regarding the outcomes, 30 patients completely recovered from CMV enteritis. Three patients died during the clinical courses because of complicated bacterial infection (n ¼ 1: present case) and post-operative infectious complications (n ¼ 2). 4. Discussion The present case, which was considered immunocompetent because there were no identifiable causes of
Fig. 2. Histological examinations of the ulcers and erosions of the ileocecal region. a) Diffuse ulcerative changes with lymphocyte-predominant inflammatory cell infiltrations and cytomegalic changes with intranuclear inclusion bodies in the mucosa and vascular endothelium were shown by by hematoxylin-eosin staining, and b) these cells were positive for CMV by immunohistochemical staining.
Please cite this article in press as: Karigane D, et al., Cytomegalovirus enteritis in immunocompetent subjects: A case report and review of the literature, J Infect Chemother (2014), http://dx.doi.org/10.1016/j.jiac.2013.12.004
D. Karigane et al. / J Infect Chemother xxx (2014) 1e5
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Table 1 Characteristics of reported cases of cytomegalovirus colitis occurring in immunocompetent individuals. Case
Age
Gender
1 2 3 4 5 6 7 8 9 10 11 12 13
35 81 36 78 68 60 68 85 67 72 67 78 79
Male Female Male Male Female Male Female Male Male Female Female Male Male
14 15 16 17 18 19 20 21 22 23 24 25
50 57 38 16 18 84 67 82 64 65 63 72
Male Female Female Female Female Female Male Male Female Female Female Female
26 27 28 29
87 88 70 72
Male Male Male Male
30 31 32 Present case
85 84 16 76 Median: 68
Male Female Female Female
Comorbidity
NTM infection
Bacterial pneumonia
Hyperthyroidism
PD PD MI, TIA
NTM infection
Symptoms
Treatment
Outcome
Reference
Diarrhea, nightsweats melena Diarrhea, hematochezia, abdominal pain Bloody diarrhea Diarrhea, abdominal pain Bloody diarrhea, abdominal pain, fever, Abdominal pain, nausea/vomiting Diarrhea, abdominal pain Diarrhea Bloody diarrhea Hematochezia, fever Bloody diarrhea Diarrhea, hematochezia, abdominal pain
Foscarnet Ganciclovir None Ganciclovir Ganciclovir None Surgical operation Ganciclovir Ganciclovir None Ganciclovir None Ganciclovir, surgical operation None None Ganciclovir Glucocorticoid Glucocorticoid Surgical operation Surgical operation Ganciclovir Ganciclovir/valganciclovir Ganciclovir None None
Recovered Recovered Recovered Recovered Recovered Recovered Recovered Died Recovered Recovered Recovered Recovered Recovered
7 8 9 10 11 12 13 14 14 15 15 16 17
Recovered Recovered Recovered Recovered Recovered Recovered Recovered Recovered Recovered Recovered Recovered Recovered
18 19 20 21 21 22 22 23 24 25 26 27
Ganciclovir Surgical operation Ganciclovir Glucocorticoid, ganciclovir, surgical operation Surgical operation Surgical operation Ganciclovir Ganciclovir
Recovered Recovered Recovered Recovered
28 29 30 31
Recovered Died Recovered Died
32 33 34 e
Diarrhea, fever, body weight loss Diarrhea, hematochezia, abdominal pain Diarrhea, fever Diarrhea Diarrhea Diarrhea, abdominal pain, fever Diarrhea, abdominal pain, fever Diarrhea, abdominal pain Diarrhea, nausea Diarrhea, nausea/vomiting Abdominal pain Diarrhea, abdominal pain, hematochezia, vomiting Diarrhea Abdominal pain Abdominal distention Diarrhea, abdominal pain Abdominal pain, vomiting Abdominal pain Diarrhea, abdominal pain, vomiting Diarrhea, abdominal pain
NTM, nontuberculous mycobacteria; PD, Parkinson disease; MI, myocardial infarction; TIA, transient ischemic attack.
immunocompromisation, presented with relatively acute-onset gastrointestinal symptoms due to CMV enteritis. Antiviral therapy with ganciclovir was initiated and improved her condition, although the patient consequently succumbed due to bacterial infectious complication. CMV enteritis/colitis is one of the manifestations of CMV diseases, which is well recognized as an opportunistic infection in association with immunocompromised states such as AIDS, solid organ or hematopoietic stem cell transplantation, and autoimmune diseases [2e6]. In general, CMV enteritis is thought to develop rarely in immunocompetent individuals, and indeed such cases have been reported only sporadically. Therefore, our experience with the present case prompted us to review the literature on CMV enteritis diagnosed in immunocompetent individuals. Although the present case developed interstitial pneumonitis during the clinical course, suggesting the possibility of impaired immune reactions, we determined the immunocompetence based on the lack of preexisting identifiable causes of immunocompromisation. Galiatsatos et al. [35] reviewed CMV enteritis histologically diagnosed in 44 immunocompetent individuals by searching cases published between 1980 and 2003 that included the term ‘CMV colitis’. Their report was the first systematic review to focus on CMV enteritis/colitis diagnosed in immunocompetent individuals, and it provided valuable findings. Although spontaneous remission of the disease was observed in 32% of the patients, advanced age, male gender, coexisting immune-modulating diseases, and colectomy were associated with a higher mortality rate [35]. However, their study had two important limitations: 1) the term ‘CMV colitis’,
which could be used interchangeably with ‘CMV enteritis’ and ‘CMV enterocolitis’, was used to search the literature; and 2) the definition of immunocompetence included coexisting immunemodulating conditions such as renal failure, diabetes mellitus, pregnancy, and untreated nonhematological malignancy. In their study, therefore, patients were subgrouped into patients with or without such conditions, and 28 cases of CMV colitis were defined as ones with intact immune systems. In addition, 10 years had passed between the last year of their literature search and the publication of their review. Thus, we attempted to refine and update the literature review of CMV enteritis/colitis in immunocompetent individuals by changing the search period to 1990e2012 to include recently published cases, extending the search terms to ‘CMV colitis’, ‘CMV enteritis’, and ‘CMV enterocolitis’, and restricting the inclusion criteria by more widely excluding the known immune-modulating or immunosuppressed conditions. In our analysis, immune-modulating or immunosuppressed conditions included diabetes mellitus, chronic kidney diseases, autoimmune diseases, malignancies, pregnancy, and surgical operation in addition to other definite states such as AIDS and organ or hematopoietic stem cell transplantation. Consequently, 32 cases fulfilled the inclusion and exclusion criteria and could be evaluated. This small number of reported cases clearly indicated the rarity of CMV enteritis in the immunocompetent population. There was no gender predominance, in contrast to the previous review [35]. However, it was consistent with the previous review that the median age of the onset of CMV enteritis was about 70 years, and that 75% of the patients were 60
Please cite this article in press as: Karigane D, et al., Cytomegalovirus enteritis in immunocompetent subjects: A case report and review of the literature, J Infect Chemother (2014), http://dx.doi.org/10.1016/j.jiac.2013.12.004
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years old or older. These results strongly suggest that aging could be a risk factor for CMV enteritis in immunocompetent individuals. Evidence has accumulated to show an association between aging and impaired immune reactions [36,37]. A component of alteration in the immune system, such as a decrease in naïve CD4 þ cells or an inverted ratio of CD4/CD8 cells and CD8þ T-cell repertoire disturbances, has been designated as an immunological risk phenotype or immune risk profile (IRP), and has been associated with aging and immunosenescence [38,39]. In addition, recent investigations have shown that CMV infection could have a significant effect on these aging-related changes in the immune system [40e42]. Therefore, it is plausible that the reactivation of latently infected CMV could further impair the immune system in the elderly and accelerate the development of CMV diseases. Recently, treatment with dasatinib, which is a potent inhibitor of BCR-ABL tyrosine kinase used for BCR-ABL-positive chronic myelogenous leukemia (CML) and acute lymphoblastic leukemia, has been associated with CMV reactivation and sporadic development of CMV enteritis [43,44]. An accumulation of cases of CMV enteritis associated with dasatinib treatment is required for a further evaluation of the risk of CMV reactivation in this specific population. Since there have been only sporadically reported cases and the previous review did not mention symptoms, symptoms associated with CMV enteritis in immunocompetent individuals have yet to be systematically assessed. Therefore, in the present review, we collected all the details about the symptoms associated with CMV enteritis in each case. The commonest symptom described was diarrhea (76%), followed by abdominal pain (52%). Hematochezia, melena, or bloody stool was described in only 27% of the patients, and fever was described in only 18%. Therefore, it is considered that macroscopic bloody stool and fever are not common symptoms and no specific symptoms were identified in association with CMV enteritis developing in immunocompetent hosts. Clinical significance of CMV antigenemia assay using the peripheral blood has not been fully evaluated in the setting of CMV enteritis. We have previously reported the limited use of CMV antigenemia in the prediction and diagnosis of CMV gastroenteritis in patients undergoing hematopoietic stem cell transplantation [6]. In the present literature review, only 3 cases, including the our case, had the descriptions of CMV antigenemia, which was positive in all 3 cases [20,28]. Because of the small of number of evaluable cases, it is difficult to draw a definite conclusion. However, the significance of CMV antigenemia in CMV enteritis may differ between immunocompromised and immunocompetent subjects. The patients in our review generally responded well to treatment for CMV enteritis, and their outcomes were favorable. No death directly related to CMV enteritis was observed, although there were 3 cases of death due to infectious complications directly or indirectly associated with treatment for CMV enteritis. For a majority of the patients, the treatment was the administration of anti-CMV agents (ganciclovir, valganciclovir, and foscarnet). In addition, 8 patients underwent surgical resection of the involved intestine, and 2 of the patients, aged 84 and 85 years died of infectious complication associated with the operation. The indication of surgical operation for CMV enteritis should be determined carefully, since it develops mainly in the elderly and the outcome of treatment with anti-CMV agents is good. Surprisingly, a spontaneous resolution of CMV enteritis was observed in 24% of the patients. Because of the lack of difference in this untreated group as compared with the treated group, it is impossible to identify the patients who do not need to be treated. However, spontaneous resolution could be a prominent feature of CMV enteritis developing in immunocompetent individuals. We conclude that CMV enteritis should be recognized as a disease entity not only in immunocompromised patients but also in
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[38] Pawelec G, Ferguson FG, Wikby A. The SENIEUR protocol after 16 years. Mech Ageing Dev 2001;122:132e4. [39] Wikby A, Mansson IA, Johansson B, Strindhall J, Nilsson SE. The immune risk profile is associated with age and gender: findings from three Swedish population studies of individuals 20e100 years of age. Biogerontology 2008;9: 299e308. [40] Chidrawar S, Khan N, Wei W, McLarnon A, Smith N, Nayak L, et al. Cytomegalovirus-seropositivity has a profound influence on the magnitude of major lymphoid subsets within healthy individuals. Clin Exp Immunol 2009;155:423e32. [41] Almanzar G, Schwaiger S, Jenewein B, Keller M, Herndler-Brandstetter D, Wurzner R, et al. Long-term cytomegalovirus infection leads to significant changes in the composition of the CD8þ T-cell repertoire, which may be the basis for an imbalance in the cytokine production profile in elderly persons. J Virol 2005;79:3675e83. [42] Pawelec G, Akbar A, Beverley P, Caruso C, Derhovanessian E, Fulop T, et al. Immunosenescence and Cytomegalovirus: where do we stand after a decade? Immun Ageing 2010;7:13. [43] Kreutzman A, Ladell K, Koechel C, Gostick E, Ekblom M, Stenke L, et al. Expansion of highly differentiated CD8þ T-cells or NK-cells in patients treated with dasatinib is associated with cytomegalovirus reactivation. Leukemia 2011;25:1587e97. [44] Sunami Y, Sato E, Ichikawa K, Yasuda H, Komatsu N. Hemorrhagic colitis caused by dasatinib following cytomegalovirus enterocolitis in a patient with chronic myelogenous leukemia in the second chronic phase. Rinsho Ketsueki 2011;52:282e6.
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