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Dr. Sylvain Bernard, MD, MSc, Raphaële Germi, PhD, Julien Lupo, PhD, Marie-
Hélène Laverrière, MD, Vincent Masse, MD, Patrice Morand, MD, PhD, Gaétan
Gavazzi, MD, PhD
PII: S1198-743X(15)00531-5
DOI: 10.1016/j.cmi.2015.05.016
Reference: CMI 270
Please cite this article as: 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 in
Apparently Immunocompetent Patients: a Case Series, Clinical Microbiology and Infection (2015), doi:
10.1016/j.cmi.2015.05.016.
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1 Original article:
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5 Sylvain Bernard MD, MSc1, Raphaële Germi PhD 2, Julien Lupo PhD2, Marie-Hélène Laverrière
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6 MD3, Vincent Masse MD4, Patrice Morand MD, PhD2, Gaétan Gavazzi MD, PhD5
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7 : Department of Infectious Diseases, Grenoble University Hospital, France
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8 Department of Virology, University Hospital, Grenoble, France - Unit of Virus Host Cell
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9 Interactions UMI 3265 UJF-EMBL-CNRS, Grenoble, France
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10 : Department of Pathology, Grenoble University Hospital, France
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11 : Microbiology and Infectious Diseases, Sherbrooke University Hospital, Qc, Canada
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12 : University Clinic of Geriatric Medicine, Grenoble University Hospital, France
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14 Corresponding author:
16 Sbernard@chu-grenoble.fr
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21 Abstract
22 CMV gastrointestinal disease rarely occurs in immunocompetent patients and is mainly diagnosis
23 based on histopathological findings. Real time PCR for CMV DNA quantification is considered
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24 as a useful diagnostic tool, but its place in the diagnostic strategy is not clearly defined.
25 To describe the clinical and paraclinical features of apparently immunocompetent patients with
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26 CMV gastrointestinal disease diagnosed by quantitative PCR results.
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27 In this retrospective study conducted in a 1500-bed tertiary care center, we have reviewed the
28 case records of apparently immunocompetent patients with positive finding of CMV DNA in
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29 gastrointestinal biopsies with compatible symptoms and endoscopic findings.
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30 A total of 13 patients were included between January 2007 and December 2010. The median age
31 was 81 years and 54% of patients had underlying immune modulating conditions. Diarrhea,
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32 hematochezia and dysphagia were the main reported symptoms and ulcers were the main
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33 endoscopic findings. The mean value of CMV DNA load in gastrointestinal biopsies was 3845
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34 copies/µg total DNA (range, 15-15500). The highest values were found in two patients who were
36 Clinical features were similar to previous series in which diagnosis was based on
37 histopathological analysis. Elderly people are more commonly affected and a link with immune
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38 senescence is possible. Quantification of CMV DNA seems to be a useful tool for diagnosis when
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39 combined with clinical and endoscopic findings, but further studies are necessary to interpret
40 quantitative values.
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43 Introduction
44 Cytomegalovirus (CMV) disease rarely occurs in people with normal immune function but is
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46 malignant diseases, intestinal bowel diseases (IBD) under treatment and patients undergoing
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48 manifestation of the disease in those patients [1,2]. Reports of GI CMV disease in
49 immunocompetent patients have been limited to several case reports and a few case series [3].
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50 Active infection in the gastrointestinal tract results generally either from endogenous reactivation
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51 or from exogenous reinfection with another virus strain [4,5]. The most common sites of GI
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52 involvement are the colon, followed by the upper GI tract [6,7]. Diarrhea, weight loss, abdominal
53 pain, dysphagia and bleeding are the main symptoms presented [8]. The spectrum of endoscopic
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54 lesions ranges from patchy erythema to deep ulcers [9]. Most reports are based on
55 histopathological analysis demonstrating active disease which is consider the gold standard for
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56 diagnosis. Diagnosis of invasive disease is not straightforward, since the presence of CMV in a
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57 diseased tissue does not necessarily imply a causal relation [10]. Quantitative real-time
58 polymerase chain reaction (rtPCR) has recently been used in a few studies to diagnose CMV GI
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59 disease particularly in IBD patients [11,12]. However, because of its high sensitivity, positive
60 results need to be combined with clinical symptoms from the upper or lower gastrointestinal
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61 tract, endoscopic findings or other technics demonstration of CMV infection in a GI tract biopsy
63 hybridization) to distinguish between latent infection and active disease [9]. Nonetheless, only a
64 few published cases combined quantitative rtPCR with clinically relevant symptoms to diagnose
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67 The aim of our study was to describe clinical features of apparently immunocompetent patients
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75 Methods
77 apparently immunocompetent adults (≥18 years old) in a 1500-bed tertiary care center during the
78 period January 2007 to December 2010. Cases were first identified from the virology laboratory
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79 database, on the basis of quantitative rtPCR positive results performed on GI tissue biopsy. All
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80 patients with CMV related clinical symptoms, macroscopic endoscopic findings, absence of other
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82 congenital immune deficiency, prior cancer therapy, haematological malignancy, organ
83 transplantation, AIDS, prolonged steroid therapy, IBD under treatment, were included in the case
84 series.
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85 Patients’ demographic characteristics, medical history, symptoms at the onset of the disease,
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86 serological status, antiviral treatment and evolution were ascertained through a manual chart
87 review. Immune-modulating conditions such as diabetes mellitus, hepatic failure, chronic renal
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92 Biopsy samples were incubated with 180µL of tissue lysis buffer (Qiagen S.A., Coutaboeuf,
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93 France) and 20µL of protein kinase for 20 min at 56°C, and lysed using the MagnaLyser
94 instrument (Roche Applied Science, Meylan, France). Total DNA from lysed biopsies was
95 extracted using the QIAamp DNA mini kit (Qiagen) according to the manufacturer’s
96 recommendations. The extraction efficiency was verified by adding an internal control to the
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97 sample and an external negative control was used to detect possible contamination. The number
98 of CMV copies was then determined from 1µg of total DNA (measured on a spectrophotometer
99 at 260/280 nm) by using real-time PCR. From 2007 to 2009 CMV DNA quantification was
100 carried out using primers and a probe targeting UL83 region (Gault et al, 2001), and the
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101 LightCycler-DNAMaster-Hybridization-Probes-Kit® (Roche Applied Science). In 2010 CMV
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102 viral load were measured using CMV R-gene quantification kit® (Argene, Verniolle, France).
103 To compare CMV real-time PCR to histological analysis, biopsies were examined for enlarged
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104 nuclei and viral inclusions and immunohistochemical staining (IHC) for CMV (monoclonal
105 mouse antibody, clone CCH2, DakoCytomation, Hamburg, Germany) were realised. CMV
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histopathological determination was confirmed if either of these methods yielded a positive result.
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107
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108 Analysis
109 We described patient characteristics using frequency, median, mean, range and summary data.
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110 Univariate analysis was performed using a Wilcoxon signed rank test with SAS software, version
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111 9.1 (SAS institute, Inc). Test of significance was two sided (P <.05).
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117 Results
119 Between January 2007 and December 2010, 17% (185/1061) of quantitative rtPCR realised on GI
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120 tract biopsies were positive, mostly in immunosuppressed patients (90%, 166/185). We finally
121 found 15 biopsies positive for quantitative rtPCR CMV in 13 apparently immunocompetent
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122 patients who had clinically relevant symptoms related to CMV (Figure 1). Patient characteristics
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123 are summarized in Table 1. The median age was 81 years (mean, 75 years; range, 54-88 years)
124 and 5 (38%) were men. Negative HIV 1 and 2 serology was retrospectively available for only 8
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125 patients (61%) however none had lymphopenia (< 1500 lymphocytes/mm3) nor was likely to
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126 have acquired immunodeficiency syndrome (risk factors). At the time of diagnosis 7 patients
127 (54%) had known immune-modulating conditions, including 4 cases of malnutrition with severe
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128 hypoalbuminemia (≤ 25g/L). The median in day of the onset of symptoms before hospitalization
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129 was 8 days (range, 1-30 days). Leukocytosis was noted in 3 cases (23%), no lymphocytosis was
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130 observed but 2 cases of lymphopenia were found for HIV negative patients. Median C-reactive
131 protein was 59 mg/L (range, 4-169 mg/L) at the time of diagnosis. Eight patients (61%) had a
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132 CT-scan which showed non specific wall thickening in 6/8 cases (75%). Case 8 had a normal CT-
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136 CMV serological status was available for 10 patients, all of them had a reactivation profile
137 (significant increase in CMV-specific IgG antibody titre with or without the presence of specific
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138 IgM antibodies). The mean CMV DNA load found in GI biopsy was 3845 copy/µg DNA
139 (median, 1150; range, 15-15500). Histopathological analysis was positive for only one patient
140 (case 12) according to the case definition. CMV DNA load in the biopsie of this patient was 2860
141 copy/µg DNA. CMV DNA load in blood was positive only in one of 4 patients (case 3).
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142
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143 Length of Stay, Antiviral Therapy and Follow-up
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144 The mean length hospital stay was 23 days (range, 2-47 days). Only one patient stayed fewer than
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145 5 days (case 6), as he was admitted solely for endoscopy. Six patients received antiviral therapy
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146 generally intravenous ganciclovir followed by oral valganciclovir for a total of three weeks of
147 treatment (4/6, 67%). Two patients had valganciclovir alone for 17 and 21 days (cases 5 and 11
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148 respectively). In treated patients, no specific complications (e.g. myelosuppression or acute renal
149 failure) warranted treatment cessation. No CMV related deaths were observed during the
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150 hospitalization period. Three cases under antiviral treatment had biopsy control with quantitative
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151 rtPCR CMV on month following the first sample. Case 7 showed complete negativation of viral
152 count and a dramatic decrease was observed for case 8 (15500 to 21 copy/µg DNA) and 12 (2860
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154
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155 Concurrent Active Immune Modulating Diseases Diagnosed after CMV GI Disease
156 In four cases (5, 7, 8, 13) diagnosis of CMV disease was followed by the diagnosis of other
157 concurrent morbidity. Two patients had persistent symptoms as well as endoscopic and
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158 histological lesions compatible with IBD (one Crohn’s disease and one ulcerative recto-colitis).
159 Case 7, was diagnosed with breast adenocarcinoma 2 months after sigmoid CMV infection. No
160 specific therapy was undertaken due to her many associated co-morbidities. Case 8 underwent
161 surgical treatment for colic adenocarcinoma with peritoneal carcinomatosis that was diagnosed
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162 during his hospital stay. These four patients had a mean CMV DNA load non-significantly higher
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163 (3262 vs 8020 copy/µg DNA, P <. .05) than other cases with available follow-up. Moreover the
164 two cases (7 and 8) with adenocarcinoma had the highest CMV DNA load (11800 and 15500
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165 copy/µg DNA respectively) on gastrointestinal biopsy.
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176 Discussion
177 This study is the first published case series of CMV GI disease in apparently immunocompetent
178 patients with diagnosis based on quantitative rtPCR CMV results. Overall, our results confirm the
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179 findings of previous case series that included ≥2 apparently immunocompetent patients with
180 diagnosis based on histology [7,16]. Table 2 compares the results of two previous case series and
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181 two reviews with those of our current study [3,5,7,16]. Elderly people (mean age: 75 years) are
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182 generally affected by the disease and the majority of cases had underlying immune modulating
183 diseases (54%). Two cases of non hematological malignancies were found in the following
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184 course of the viral infection. These cases had the highest CMV load of the case series.
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185 Several factors could explain why elderly people are more frequently affected. Aging is
186 associated with a decline in immunological function, a concept termed “immune senescence”. It
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188 cells. It is a phenomenon of decreased function, involving changes to both innate and adaptive
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189 immunity and an imbalance between the two arms [17]. Reports have showed that it probably
190 increases infectious morbi-mortality [18]. CMV has been implicated in immune senescence
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191 mechanisms: latent CMV infection leads to a continuous production of viral proteins and, as a
192 consequence to chronic antigenic stimulation, accelerates the exhaustion of the naïve T cell pool,
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193 especially in the absence of adequate T cell renewal from the thymus [17,19]. Poor T cells
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194 response is particularly implicated in viral reactivation of herpesviruses [18]. In our case series,
195 CMV may be a cause of immune senescence or also a consequence of this senescence as a
196 disease manifestation precipitated by other underlying immune modulating conditions such as
197 cancer. Clinical manifestations could reflect the imbalance of the homeostatic control of
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198 persistent viral infections caused by CMV. Co-morbidities also had an impact on infectious
199 diseases encountered in elderly patients, particularly immune modulating conditions such as
200 diabetes or malnutrition [20]. Previous studies showed that immune modulating conditions were
201 frequently associated with CMV GI disease (36-40%) [3,5]. In our study, only 5 cases were free
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202 of immune modulating conditions and only one case (case 10) was free of any comorbidity [3,5].
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203 Also the understanding of immune senescence in elderly people should leads to reconsider the
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205 observed that mean age was lower in reviews (Table 2) because cases of primary infection were
206 included [3,5]. In our and other published case series on CMV GI disease for which CMV
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serological status was available no cases of primo infection were found which is consistent with
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208 the high seroprevalence (90%) found in persons older than 80 years [7,19,21].
209 Although histology is considered the gold standard for the diagnosis of CMV gastrointestinal
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210 disease, it suffers from many limitations, notably a lack of sensitivity and dependence on sample
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211 quality and the examiner’s experience [22]. The automated molecular assays were introduced a
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212 few years ago and seem to yield reliable results [8]. Recent studies reported that CMV DNA
213 quantification in GI biopsies could be useful to diagnose CMV GI disease but well defined cut
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214 off need still to be validated to improve specificity of this test [23,24]. One work aimed to
215 interpret CMV DNA quantification in 163 lower intestinal biopsy from immunocompromised
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216 patients. Results of this study supposed that histopathology alone was not enough sensitive as
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217 suitable gold standard [11]. Therefore Ganzenmueller et al established cut-off intestinal CMV
218 DNA load predictive for CMV intestinal disease by using histopathological or clinical criteria as
219 gold standard to attribute intestinal illness to CMV. Applying these cut off to our results, we can
220 suggest that 6 patients fit the clinical definition whereas no one corresponds to the histological
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221 diagnosis. These cut off values were defined for patients with underlying immune deficiency
222 conditions, we can hypothesize that higher level of CMV replication is observed in these patients
223 as it was previously described for CMV viral load in peripheral blood leukocytes during CMV
224 primary infection [25]. Even if histopathologic testing cannot be replaced quantification of CMV-
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225 DNA in intestinal biopsy by rtPCR is a useful diagnostic tool with high sensitivity, this method is
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226 objective, fast and highly standardized. In cases of negative histopathological results, CMV
227 associated disease should be diagnosed on clinical grounds (symptoms, endoscopic lesions,
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228 absence of other pathogens) in combination with detection of virus by quantitative rtPCR [11].
229 The main challenge with quantitative rtPCR CMV on gastrointestinal biopsy remains
230
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interpretation of quantitative positive results. Further studies are needed to evaluate the value of
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231 GI CMV DNA load in different population sources with different degrees of immune deficiency
233 As in previous study, CMV DNA load in blood was negative for 75% patients (n=4) suggesting a
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235 Efficacy of treatment could not be assessed because of our small number of cases, limited follow-
236 up and because patients who received specific therapy probably had more severe disease. No
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237 previous study (Table 2) evaluated efficacy of treatment, we noted that spontaneous remission
238 varied between 32 to 70%. Mortality is difficult to assess because of several potential bias such
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239 as comorbidities, malnutrition and low functional status particularly in elderly patients.
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240 Two cases of CMV GI disease were associated with IBD diagnosis during the same
241 hospitalization. CMV has been reported to assume a triggering role in the onset or worsening of
242 IBD exacerbations and a part in steroid refractoriness [12]. No clear guidelines are proposed for
243 therapeutic management in these situations. It is now believed that one-third of all new cases of
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244 Crohn’s disease occur in the elderly population. Misdiagnosis at the initial presentation is more
245 common in the elderly (60 % compared with 15 % of the younger population). Delay in diagnosis
246 is also longer (up to 6 years in the elderly compared with 2 years in the younger IBD patients)
247 [28].
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248 Two cases of solid malignancies have followed diagnosis of CMV GI disease. Link between viral
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249 infection and GI cancer was studied but results are controversial. A recent study conducted on 56
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250 colorectal biopsies of different cancer phenotypes suggested no evidence of a direct association
251 between CMV and colorectal cancer [29]. In our series, CMV infections reached the digestive
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252 tract but cancer was diagnosed at a distant site. The impact of cancer on immune system could
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253 have led to a CMV reactivation. We noted that these two cases had the highest CMV DNA load
254 in GI biopsy. No conclusions can be drawn, but further evaluation should be undertaken to
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255 evaluate if patients with high CMV DNA load warrant extensive cancer workup.
256 Limitations of our work are mainly linked to its retrospective nature. The small number of cases,
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257 missing data and limited follow up hamper conclusions that can be drawn.
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258 Our work confirms the few clinical data for this rare disease that affect mainly elderly patients.
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259 Because there is a specific link between CMV infection and ageing it should be of interest to
260 study more extensively symptoms and outcome of CMV infection in elderly patients.
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261 Quantitative rtPCR for CMV DNA seem to be an accurate tool for diagnosis (if associated with
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262 compatible clinical and endoscopic lesions to avoid overdiagnosis due to the possible detection of
263 latent CMV) with a higher sensitivity than histology that may help to better diagnose CMV
264 infection.
265
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267 Acknowledgments
268 None
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269 Author contributions:
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270 SB: study concept and design, acquisition of subjects and data, analysis and interpretation of
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272 RG, JL, PM: technical support for virological analysis, analysis and interpretation of data.
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26. Mori T, Mori S, Kanda Y, et al. Clinical significance of cytomegalovirus (CMV) antigenemia
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27. Ruell J, Barnes C, Mutton K, et al. Active CMV disease does not always correlate with viral
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28. Katz S, Pardi DS. Inflammatory Bowel Disease of the Elderly: Frequently Asked Questions (FAQs).
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29. Bender C, Zipeto D, Bidoia C, et al. Analysis of colorectal cancers for human cytomegalovirus
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Figure Legend
Figure 1. Flow chart of CMV quantitative Real Time PCR realised on gastrointestinal biopsy
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between January 2007 to December 2010.
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rtPCR : real time PCR, IBD : Inflammatory Bowel Diseases, AIDS: acquired immunodeficiency
syndrome.
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*under treatment
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Figure
Figure 1.
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Gastrointestinal biopsy
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185 positive results
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immunocompromised patients
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Haematological malignancies: 17
Transplant organ: 19
Solid neoplasic: 4
AIDS : 5
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Others : 15
19 positive rtPCR for 17
immunocompetent patients
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endoscopic findings
immunocompetent patients
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(n=10) (n=11) (n=13) (n=15) (n=44)
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Sex (F) ,% 90 22 54 33 16
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Immune modulating NA NA 54 40 36
conditions (%)
Upper digestive 0 45 38 0 0
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tract involvement
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(%)
Diagnosis method Histology Histology Quantitative Histology Histology
rtPCR
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Primo-infection (%) 0 NA 0 47 29
Spontaneous 70 NA 54 NA 32
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remission (%)
Other immune 0 4 neoplasia 2 IBD and 2 3 IBD NA
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NA:Non Available, IBD : Inflammatory Bowel Diseases, rtPCR : real time PCR
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1 69/M Type 2 diabetes/1 Fever and Sigmoid ulcer - Reactivation
diarrhea profile
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2 83/F Diabetes mellitus, Hematemesis Oesophageal ulcer - Not realised
chronic renal failure/2 with confluent
erosions
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3* 71/M No IM conditions/8 Diarrhea Rectal petechiae Rectal and colic Reactivation
and whitish plaques wall thickening profile
4 88/F Chronic renal failure, Hematochezia Rectal ulcer (3cm) Infiltration of pre- Reactivation
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malnutrition/3 sacral region profile
13 56/F Malnutrition/3 Fever and chronic Deep sigmoid Ileo-colic wall Reactivation
diarrhea ulcers thickening profile
Patient CMV DNA Histology Therapy after diagnosis (length in Length Other active Follow up
Load (copy/µg day) hospital stay concurrent (Relapse and
DNA) (days) disease mortality during
hospitalzation)
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2 2675 Negative Supportive treatment 27 No NA
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valganciclovir PO (24) surviving
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valganciclovir PO (7)
5 2860 Positive Valganciclovir PO (17) 33 Refractory No relapse,
ulcerative colitis surviving
needed total
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colectomy
6 1074 Negative Supportive treatment 2 No NA
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7 11800 Negative Ganciclovir IV (3) then 47 Breast No relapse,
valganciclovir PO (21) adenocarcinoma surviving
treatment
13 1920 Negative Supportive treatment 10 Crohn’s disease No relapse,
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surviving