Accepted Manuscript

Symptomatic Cytomegalovirus Gastrointestinal Infection with Positive Quantitative

Real Time PCR in Apparently Immunocompetent Patients: a Case Series

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

To appear in: Clinical Microbiology and Infection

Received Date: 17 December 2014

Revised Date: 26 April 2015
Accepted Date: 11 May 2015

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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 ACCEPTED MANUSCRIPT

1 Original article:

2 Symptomatic Cytomegalovirus Gastrointestinal Infection with Positive Quantitative Real

3 Time PCR in Apparently Immunocompetent Patients: a Case Series

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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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1
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:

15 Dr. Sylvain BERNARD

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16 Sbernard@chu-grenoble.fr
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17 Infectious Diseases unit

18 CHU Grenoble BP217

19 38043 Grenoble Cedex 9

20 Telephone: +33 (0) 476766571 / Fax: +33 (0) 476768998

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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

35 diagnosed with adenocarcinoma in the following course of CMV infection.

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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.

41 Keywords : Cytomegalovirus, oesophagitis, colitis, PCR, immuno senescence.

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43 Introduction

44 Cytomegalovirus (CMV) disease rarely occurs in people with normal immune function but is

45 more commonly diagnosed in immunosuppressed patients (especially HIV, transplant recipients,

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46 malignant diseases, intestinal bowel diseases (IBD) under treatment and patients undergoing

47 chemotherapy or steroid therapy); gastrointestinal (GI) involvement is a classical and frequent

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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

62 specimen (by culture, histopathologic testing, immunohistochemical analysis, or in situ

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

65 CMV GI disease [13-15].

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67 The aim of our study was to describe clinical features of apparently immunocompetent patients

68 with a diagnosis of CMV GI disease based on quantitative rtPCR on GI biopsy, clinical

69 symptoms and endoscopic findings.

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75 Methods

76 We performed a retrospective descriptive case series of symptomatic CMV GI infection in

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

81 digestive pathogens and no apparent immunodeficiency at the time of diagnosis such as

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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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88 failure, malnutrition (with related severe hypoalbuminemia), non-haematological malignancies

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89 and autoimmune diseases were also recorded.

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91 Quantitative real-time PCR for CMV DNA:

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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

118 Patient Characteristics, Clinical Manifestations, Endoscopic and Radiological Features

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-

133 scan at the site of CMV disease.

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135 Diagnostic Strategies

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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153 to 54 copy/µg DNA).

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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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187 refers to impairment in immunity as a result of age-associated changes in function in a variety of

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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

204 presumed immunocompetence of this population particularly regarding CMV infection. We

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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

232 amongst clinical symptoms and severity.

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233 As in previous study, CMV DNA load in blood was negative for 75% patients (n=4) suggesting a
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234 localized replication in the digestive tract only [26,27].

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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.

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266 The authors declare no conflicts of interest.

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

271 data, and preparation of manuscript.

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272 RG, JL, PM: technical support for virological analysis, analysis and interpretation of data.

273 MHL: technical support for pathology analysis.

274 VM: analysis and interpretation of data.

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275 GG: study concept and design, acquisition of subjects and data, analysis and interpretation of data,
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276 and preparation of manuscript.

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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.

1061 CMV rtPCR on

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Gastrointestinal biopsy

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185 positive results

166 positive rtPCR for 110

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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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4 rtPCR for 4 patients with other

causative pathogens or non-
compatible macroscopic
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endoscopic findings

15 positive rtPCR for 13

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immunocompetent patients
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Table 2. Previous Published Case Series On CMV Gastrointestinal Disease In Immunocompetent

Patients.
Case series Reviews

Ng et al Maionara et Our current Klauber et al Galiatsos et

7 15 3
Variable (1999) al (2003) study (1998) al (2005)5

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(n=10) (n=11) (n=13) (n=15) (n=44)

Age in years (mean) 71 72 75 57 61

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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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modulating diseases neoplasia

diagnosed after
CMV
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NA:Non Available, IBD : Inflammatory Bowel Diseases, rtPCR : real time PCR
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Table 1. Characteristics of 13 Immunocompetent Cases of CMV Gastrointestinal Disease:

Patient Age in Immune modulating Clinical Endoscopy findings Tomodensitometry CMV Serological
years/sex (IM) conditions/ number manifestations on site of positive status
of other comorbidities biopsy

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1 69/M Type 2 diabetes/1 Fever and Sigmoid ulcer - Reactivation
diarrhea profile

RI
2 83/F Diabetes mellitus, Hematemesis Oesophageal ulcer - Not realised
chronic renal failure/2 with confluent
erosions

SC
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

U
malnutrition/3 sacral region profile

5 80/F No IM conditions/4 Bloody diarrhea Deep sigmoid - Reactivation

AN
ulcers profile

6 83/M No IM conditions/5 Dysphagia Oesophageal ulcer - Not realised

with stenosis
M

7 84/F Type 1 diabetes, Fever and Wide sigmoid Sigmoido-rectal Reactivation

malnutrition/4 diarrhea ulcers wall thickening profile
D

8 83/M No IM conditions/6 Dysphagia, Ulcerative Normal sus- Reactivation

hematemesis oesophagitis diaphragmatic profile
TE

9 54/M Chronic alcoholism/3 Dysphagia, Necrotical Oesophageal wall Reactivation

hematemesis oesophagitis thickening profile
(13mm)
10* 65/F No IM conditions/0 Hematochezia Multiple rectal Sigmoid wall Not realised
ulcers thickening (9mm)
EP

11 81/F Malnutrition/4 Fever and Duodenal erosion Dudodenal and Reactivation

diarrhea colic wall profile
thickening
C

12 84/M No IM conditions/3 Dysphagia Severe oesophagitis - Reactivation

profile
AC

13 56/F Malnutrition/3 Fever and chronic Deep sigmoid Ileo-colic wall Reactivation
diarrhea ulcers thickening profile

*symptoms appeared after the onset of hospitalization

NA: Non available follow-up
 ACCEPTED MANUSCRIPT

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)

1 1150 Negative Supportive treatment (probabilist 5 No No relapse,

antibiotherapy) surviving

PT
2 2675 Negative Supportive treatment 27 No NA

3 11750 Negative Ganciclovir IV (3), then 18 No No relapse,

RI
valganciclovir PO (24) surviving

4 918 Negative Ganciclovir IV (5) then 42 No NA

SC
valganciclovir PO (7)
5 2860 Positive Valganciclovir PO (17) 33 Refractory No relapse,
ulcerative colitis surviving
needed total

U
colectomy
6 1074 Negative Supportive treatment 2 No NA
AN
7 11800 Negative Ganciclovir IV (3) then 47 Breast No relapse,
valganciclovir PO (21) adenocarcinoma surviving

8 15500 Negative Ganciclovir IV (5) then 19 Adenocarcinom No relapse,

M

valganciclovir PO (16) a of sigmoid surviving

with peritoneal
carcinosis
D

9 173 Negative Supportive treatment 26 No NA

TE

10 15 Negative Supportive treatment 41 No NA

11 64 Negative Valganciclovir PO (21) 14 No No relapse,

surviving
EP

12 84 Negative Supportive treatment 15 Occlusive No relapse,

syndrom, surviving
resolutive with
medical
C

treatment
13 1920 Negative Supportive treatment 10 Crohn’s disease No relapse,
AC

surviving

NA:Non Available, IV : intravenous, PO : per os