Journal of Experimental Biology and Agricultural Sciences, October - 2015; Volume – 3(V)

Journal of Experimental Biology and Agricultural Sciences

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ISSN No. 2320 – 8694

CYTOMEGALOVIRUS INFECTION AS A POSSIBLE CAUSE OF OGILVIE'S SYNDROME: A CASE REPORT AND REVIEW OF THE LITERATURE

1,* 2 Magdalena Fernández García and Marcos Noé Madrid

1Department of Internal Medicine, Hospital Marqués de Valdecilla, University of Cantabria, Santander, Spain 2Family Medicine, Centro de Salud General Dávila, Santander, Spain

Received – September 02, 2015; Revision – September 19, 2015; Accepted – October 14, 2015 Available Online – October 20, 2015

DOI: http://dx.doi.org/10.18006/2015.3(5).471.478

KEYWORDS ABSTRACT Colonic pseudo-obstruction

Ogilvie's syndrome is an uncommon condition with a heterogeneous etiology. The mechanism is poorly Ogilvie's syndrome understood and likely multifactorial. An imbalance between the parasympathetic and the sympathetic Cytomegalovirus infection innervations of the intestine as well as an abnormal response against gut commensal bacteria are thought to be the main causes. We present the case of an apparently immunocompetent female patient with an Myenteric plexus infection Ogilvie's syndrome associated with cytomegalovirus infection.

Enterocolitis

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1 Introduction Present study reports the case of an apparently immunocompetent female patient with an Ogilvie's syndrome Acute colonic pseudo-obstruction, or Ogilvie's syndrome, associated with cytomegalovirus (CMV) infection. Besides, a occurs when symptoms and signs of intestinal obstruction of brief review of the literature on Ogilvie's syndrome with CMV the small or large bowel appears in the absence of a involvement is also presented. mechanical cause. It is typically reported in hospitalized or institutionalized patients with underlying severe illness or after 2 Case Report surgery (Vanek & Al-Salti, 1986). Sometimes infections (Tanida et al., 2013; Charatcharoenwitthaya et al., 2014), A 71 year-old female was admitted in to the Department of metabolic imbalances (Sunnoqrot & Reilly, 2015) or different Internal Medicine, Hospital Marqués de Valdecilla, University medications are involved in its origin (Cappell, 2004). of Cantabria, Santander, Spain in October 2013 because of Potential severe consequences as colonic spontaneous abdominal pain. Her medical history included diabetes mellitus perforation, colonic or intestinal bleeding may appear type 2 with non-proliferative diabetic retinopathy, chronic liver in its evolution. disease, Child A, secondary to ethanol consumption,

Table 1 Main biochemical laboratory results in the reported patient

PARAMETER (units) Result Reference Range PERIPHERAL BLOOD White blood cell count (x 103) 4.8 4.8 - 10.8 Neutrophils (%) 46 42.0 - 75.0/ Lymphocytes (%) 5.0 20.0 - 51.0 Band cells (%). 27 _ Metamyelocytes (%) 2 _ Platelets (x 103) 120 150 - 450 x 103 ESR (mm/1sth) 40 1.0 - 15.0 CRP (mg/dl) 10 0.1 - 0.5 Procalcitonin (ng/mL) 4 < 0.5 BIOCHEMISTRY Amylase (U/L) 51 1 - 100 Albumin 3 3.2-5.3 Prothrombin time (%) 57 70 - 100 ALT (U/L) 33 2 - 40 AST (U/L) 58 1 - 37 GGT(U/L) 18 7 - 32 Alkaline phosphatase (U/L) 49 40 - 129 Total bilirubin (mg/dL) 0.7 0.1 - 1.2 HYDROSALINE METABOLISM STUDY Creatinine (mg/dl) 1.4 0.50 - 1.20 Urea (mg/dL) 86 5 - 50 Sodium (mEq / L) 128 135 - 145 Potassium (mEq / L) 2.2. 3.5 - 5.0 GFR (MDRD-4) ml/min/1,73 m2 42 >60.00 Serum aldosterone (pg/ml) 10 10 - 310 PHOSPHO-CALCIC METABOLISM STUDY Serum calcium (mg/dL) 6.5 8.1 - 10.4 Ionized calcium (mM) 1.12 1.16 - 1.30 Ionic normalized calcium (mM) 1.15 1.16 - 1.30 i PTH (pg/ml) 51 10 - 45 25-OH-vitamin D (ng/ml) 24 20 - 60 Phosphorus (mg/dL) 2.8 2.3 - 4.0 Magnesium (mg/dL) 2.1 1.7–2.4 [Abbreviations: ESR: Erythrocyte sedimentation rate; CRP: Chain reaction polymerase; GFR: Glomerular Filtration Rate; ALT; Alanine aminotransferase AST; aspartate aminotransferase; GGT: gamma glutamyl transpeptidase ; i PTH: intact parathyroid hormone]

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Cytomegalovirus infection as a possible cause of Ogilvie's syndrome: A case report and review of the literature. 473

Figure 1 Abdominal X-ray on admission: Diffuse dilatation of intestines and thickened colonic wall.

Figure 2 Abdominal computed tomography scan findings: Dilation of the whole colonic frame. Diffuse thickening of the wall of the and sigmoid colon, without observing regional inflammatory changes, associated collections or masses. anxiety disorder, chronic L4-L5-S1 radiculopathy and a On admission, the patient was hemodynamically stable. Her kyphoplasty due to T12 vertebral fracture three years before temperature was 37ºC, blood pressure was 110/70 mmHg, admission. She denied any tobacco or illicit drug use. She was heart rate was 108 b.p.m and respiratory rate was 22 breaths on metformin, spironolactone, omeprazole, pregabalin, per minute. The patient complained about abdominal pain to clonazepam, alendronate and calcium carbonate plus palpation in the entire abdomen and in the auscultation, cholecalciferol treatment. She referred a history of chronic hypoactive bowel sounds were present. Abdominal X-ray on exacerbated for the last two weeks with admission showed diffuse dilatation of intestines and thickened progressive increase in abdominal perimeter without emission colonic wall (Figure 1). Rectal examination was normal and of gas or feces. In the emergency ward, watery stools without the nasogastric aspirate was clear, without blood or fecaloid pathological products were objectified as well as profuse content. Discontinuation of oral intake, intravenous fluid episodes of and emesis. replacement and piperacillin-tazobactam treatment were started.

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Figure 3 Endoscopic findings: Extense area of edema, erythema and friable mucosa, with multiple lineal fibrinous-based ulcers.

Table 1 summarizes the main laboratory studies conducted. gastrointestinal endoscopy was performed too, showing Despite the general condition of the patient was good, profuse grade I. watery and vomiting persisted. A severe electrolyte imbalance, not present on admission lab-determinations Table 2 shows the microbiological and immunological studies appears. Arterial blood gases showed a pH of 7.28, pCO2 39.1 performed. Histopathological examination of the colonic mm Hg, bicarbonate of 17.1 mEq/l and a BE of -8.700, biopsy showed an intense acute and chronic inflammation in compatible with a simple metabolic acidosis. A significative the lamina propria and granulation tissue but no intranuclear hypokalemia (2.2 mEq / L) and hypocalcemia (6.6 mEq / L) inclusions were observed. A PCR method to detect human lead us to the infusion of potassium chloride and calcium herpesvirus and enterovirus (Clart Entherpex, Genomica SAU, gluconate, with serum potassium and calcium concentrations Madrid, Spain) was used in the specimen from the maintained in the 3.5 mEq /l and 7.8 mg/dL, respectively. colonoscopic biopsy. The molecular analysis was positive for CMV, and the diagnosis of CMV infection was established. An abdominal computed tomography scan objectified the presence of morphological changes related to liver On the twelfth hospital day intravenous ganciclovir was started and perihepatic ascites. Cholelithiasis, without parietal or at induction dose (5 mg/kg/12h) during the first week. Then, regional inflammatory signs and no dilatation of the bile ducts the patient completed 4 weeks of maintenance dose treatment were observed. (5/mg/kg/24h). The clinical outcome was favourable with the normalization of gastrointestinal transit and the resolution of A striking dilation of the whole colonic frame was present, the colonic pseudo-obstruction. Three months later, a new from the cecal area to the rectal ampulla, accompanied by a control ileo- was performed and biopsies were diffuse thickening of the wall of the rectum and sigmoid colon, taken again. In this case, the molecular analysis was negative without observing regional inflammatory changes, associated for CMV. collections or masses. No contrast defects were identified in the mesenteric artery or vein. There was no sign of intestinal Discussion pneumatosis which may suggest mesenteric ischemia. No significant dilatations of the small bowel loops were present Ogilvie (1948) first described this syndrome in association (Figure 2). The diagnosis of Ogilvie’s syndrome was with retroperitoneal malignancy infiltration of the celiac established and nasogastric and rectal tubes were placed, plexus. Today, its precise mechanism is still unknown but the improving both, and, partially, emesis so most plausible and accepted theory suggests an impairment of oral erythromycin was added as a prokinetic treatment. the with an increased sympathetic activity and/or decreased parasympathetic activity (Turnage et A complete exploratory ileo-colonoscopy was performed al., 2006). Intestinal pseudo-obstruction secondary to CMV (Figure 3) and in this neither strictures nor were infection has not been often described in the literature. identified. Near the splenic flexure, endoscopy showed an area Infection of the myenteric plexus is proposed as the of about 8 cm of edema, erythema and friable mucosa with pathophysiologic mechanism leading to an imbalance in the multiple lineal fibrinous-based ulcers. Biopsies of this portion autonomic nervous system of the colon in this cases but it is were collected. As the endoscope was withdrawn, a important to notice that the CMV myenteric plexus infection, colonoscopic decompression was performed. An upper when present, does not necessarily cause digestive motor dysfunction (Press et al., 1980).

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Cytomegalovirus infection as a possible cause of Ogilvie's syndrome: A case report and review of the literature. 475 Table 2 Microbiologic and immunologic results in the reported patient

MICROBIOLOGIC STUDIES RESULT BLOOD CULTURE (x·6) Negative STOOL CULTURE Aeromonas Negative Campylobacter Negative Salmonella Negative Shigella Negative Vibrio Negative Yersinia Negative Clostridium difficile toxin Negative UROCULTIVE Negative SEROLOGIES HIV 1/2 Negative CMV (IgM) Negative CMV (IgG) Negative IMMUNOLOGIC STUDIES ASCA (IgA) Negative ASCA (IgG) Negative ANA Negative ANCA Negative [HIV: human immunodeficiency virus; CMV: Cytomegalovirus; ASCA: anti-Saccharomyces cerevisiae antibodies ANA: antinuclear antibodies; ANCA: anticytoplasm of the neutrophil antibodies]

A PubMed research introducing the terms “Ogilvie’s disorders (Isik et al., 2013; Katzir et al., 2014; Yasa et al., syndrome”, “CMV infection” and/or “” and/or 2014), and certain sedative medications (Cappell, 2004), may “myenteric plexus infection” was performed and a total of six contribute to the development of Ogilvie’s syndrome. In the entries were obtained (Press et al., 1980; Sonsino et al., 1984; present study the patient was diagnosed with chronic L4-L5-S1 Deziel et al., 1990; Shrestha et al., 1996; Shapiro et al., 2000; radiculopathy treated with pregabalin, an anxiety disorder Charatcharoenwitthaya et al., 2014). A total of seven cases of treated with clonazepam and a diabetes mellitus type 2 with Ogilvie’s syndrome associated to CMV infection were found. potential microvascular complications. All these conditions Table 3 summarizes the published cases of Ogilvie’s syndrome may affect the normal enteric propulsion and cause associated to CMV infection. uncoordinated intestinal muscle contractions.

Initial laboratory determinations showed a severe We find of special interest and relevance to point that, lymphocytopenia which was reported for the first time in the according to the actual definition of CMV infection, this case present study and was not been reported in previous tests. In does not fulfil the criteria for CMV . the present study, we attribute this low lymphocytes level to a The current papers establish the need of the coexistence of a transient sepsis-induced immunosuppression, supported by the combination of “clinical symptoms from the gastrointestinal procalcitonin and calcium levels on admission. tract, findings of macroscopic mucosal lesions on endoscopy, Notwithstanding, other causes of lymphocytopenia such viral present both in our patient and demonstration of CMV infections; renal failure or even an inflammatory bowel disease infection by culture, histopathological testing, flare could be considered in this patient. In the same manner, immunohistochemical analysis, or in situ hybridization in a the renal insufficiency present on admission in the setting of biopsy specimen” (Ljungman et al., the intra-abdominal sepsis resolved with the administration of 2002). In present study, CMV was detected only by a PCR in intravenous fluid and piperacillin-tazobactam. the colonic biopsy and this method is considered insufficient for the diagnosis of CMV gastrointestinal disease. However Electrolyte disturbances, such as hypokalemia, hyponatremia this issue is controversial. In a recent review of CMV detection and hypocalcemia might act as contributing factors in in the immunocompetent host with , conducted by Ogilvie’s syndrome. However, this imbalance is often the Goodman et al (2015), the authors argue that “studies are result of third-space fluid shifts and due to the needed in order to clearly define the significance of a positive pseudo-obstruction rather than the cause of it (Saunders & CMV in the bowel”. They also suggest the convenience to Kimmey, 2005). It is noteworthy that laboratory establish a diagnostic cut-off CMV-DNA level in the colon determinations returned to the normal range with the resolution samples to determine the candidates from antiviral treatment. of the colonic pseudo-obstruction. The presence of neurologic

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Table 3 Published cases of Ogilvie’s syndrome associated to CMV infection

Author Year Sex Age Clinical setting Clinical findings Endoscopy findings CMV detection Treatment Outcome (M/F) (yrs) Press et al. 1980 M 18 Renal transplantation NA NA Intestinal biopsy NA Death

Sonsino et al. 1984 M 2 NS Abdominal distention, diarrhea No endoscopic studies Rectal biopsy: Inflammatory cells, NS NS month- and dehydration performed Myenteric-neuron nuclear inclussions. old Viruria and specific IgM and IgG antibodies as confirmative tests Deziel et al. 1990 M 26 HIV infection NS NS NS Right hemicolectomy, Death small bowel resection, ileostomy Shrestha et al. 1996 F 69 10-weeks renal transplantation Colicky abdominal pain, Inflamed rectum and Sigmoid biopsy: Intranuclear inclusions Ganciclovir e. v (5 Resolution diarrhea, dehydration and sigmoid colon surrounded by a distinct halo mg/kg/12 h) abdominal distention Positive antigenaemia as confirmative test Shapiro et al. 2000 M 43 Liver transplantation due to Massive colonic and small Intact colonic mucosa CMV antigenemia and IgM test Ganciclovir e.v (initial Resolution end-stage cirrhosis secondary bowel dilatation with no perforation positive dose 2.5 mg/kg/12h on to C and remote visible account of neutropenia alcohol abuse F 24 Liver transplantation due to Marked abdominal distention No endoscopic studies CMV antigenemia positive. Ganciclovir e.v (5 Resolution acetaminophen-induced with adynamic performed (seroconversion) mg/kg per day x 10 fulminant hepatic failure days) (grade IV) and 20 weeks pregnant Charatcharoenwitthaya et al. 2014 F 38 Pregnancy Generalized abdominal Multiple large clean- Colonic biopsy: Granulation tissue Ganciclovir e.v (dose Resolution (primigravida) distention, absent bowel based ulcers with well- containing cytomegalic cells with NS) sounds, diffuse dilatation of defined border in the intranuclear inclusions (confirmed by intestines and thickened sigmoid colon immunoperoxidase staining) colonic wall Present Study 2015 F 71 Diabetes mellitus type 2 Chronic constipation Edema, erythema and Colonic biopsy: PCR positive. Ganciclovir e. v (5 Resolution Chronic , Child A exacerbated the last two weeks friable colonic mucosa mg/kg/12 h) L4-L5-S1 radiculopathy Generalized abdominal with multiple lineal distention, absent bowel fibrinous-based ulcers sounds, watery stools

[NA: Not available; NS: Not specified]

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Cytomegalovirus infection as a possible cause of Ogilvie's syndrome: A case report and review of the literature. 477 We want to highlight the fact that only two of the seven pseudo-obstruction. Likewise, further studies on the reported cases found in our research fulfil the three criteria significance of CMV PCR in the immunocompetent host with proposed by Ljungman et al. (2002) for the CMV colitis are needed to advance in the correct interpretation of gastrointestinal disease (Shrestha et al., 1996; this test. Charatcharoenwitthaya et al., 2014). Conflict of interest Another interesting question to point is that CMV IgG and IgM in this patient were both negative. It is well known that in Authors would hereby like to declare that there is no conflict of immunosuppressed patients CMV colitis is often secondary to interests that could possibly arise. the reactivation of a latent infection while in the immunocompetent host CMV colitis can occur as a primary References infection (Orenstein & Dieterich, 2001). We find improbable, although unusual, a reactivation of a latent infection because of Cappell MS (2004) Colonic toxicity of administered drugs and the negativity of the IgG, the age (the prevalence of CMV chemicals. The American Journal of specific antibody increases with age) and the comorbidities 99:1175-1190. doi:10.1111/j.1572-0241.2004.30192.x. present in our patient. Another possible explication is an eventual seroconversion at time of diagnosis but we do not Charatcharoenwitthaya P, Pausawasdi N, Pongpaibul A (2014) perform a second determination to assess this possibility Gastrointestinal: Ogilvie's syndrome: A rare complication of (Klauber et al., 1998). Furthermore, a lab error was possible cytomegalovirus infection in an immunocompetent patient. too. Journal of Gastroenterology and 29: 1752. doi: 10.1111/jgh.12760. The clinical outcome in our patient was favorable once ganciclovir was started. We must keep in mind that this Chiva M, Guarner C, Peralta C, Llovet T, Gómez G, Soriano antiviral can cause myelosuppression and need dose G, Balanzó J (2003) Intestinal mucosal oxidative damage and adjustments in renal impairment situations. We do not use bacterial translocation in cirrhotic rats. European Journal of intravenous neostigmine (Ponec et al., 1999) in order to avoid Gastroenterology & Hepatology 15:145–150. its adverse effects (, hypotension) and due to the impossibility of a continuous cardiac monitoring in an Deziel DJ, Hyser MJ, Doolas A, Bines SD, Blaauw BB, intensive care unit. Neostigmine was administered only in one Kessler HA (1990) Major abdominal operations in acquired of cases found in our research without clinical response immunodeficiency syndrome. The American Surgeon 56:445- (Charatcharoenwitthaya et al., 2014). So, we administered the 50. first dose of ganciclovir on the twelfth hospital day, when creatininie levels where 0.8 mg/dL (GFR 68 ml/min/1,73 m2, Goodman AL, Murray CD, Watkins J, Griffiths PD, Webster MDRD-4) and the initial lymphocytopenia had been resolved. DP (2015) CMV in the gut: a critical review of CMV detection in the immunocompetent host with colitis. European Journal of We must not avoid mentioning that the presentation of CMV Clinical Microbiology & Infectious Diseases 34:13-18. colitis may mimic an flare. In our case, the doi:10.1007/s10096-014-2212-x. result of the biopsy, the serologies and the good clinical outcome after ganciclovir administration, led us to consider our Isik AT, Kolukisa M, Ergun F, Ahmad IC (2013) Ogilvie's patient´s pseudo colonic obstruction as an Ogilvie's syndrome syndrome in an elderly patient with multi-system atrophy. associated with CMV infection. Clinical Autonomic Research 23:155-156. doi: 10.1007/s10286-013-0192-z. Finally, our patient was diagnosed with chronic liver disease. We find interesting to mention the relation between the liver, Katzir M, Abeshaus S, Attia M, Zaaroor M (2014) Ogilvie's the gut microbiota and the immunological defense in cirrhotic syndrome following ventriculoperitoneal shunt surgery for patients. Changes in gut bacterial species in patients with normal pressure hydrocephalus. Acta Neurochirurgica cirrhosis have been shown to impair intestinal immune 156:787-788. doi: 10.1007/s00701-014-2014-z. homeostasis and immunological host defense mechanisms, predisposing these patients to opportunistic infections (Chiva Klauber E, Briski LE, Khatib R (1998) et al., 2003). in the immunocompetent host: an overview. Scandinavian Journal of Infectious Diseases 30:559-564. DOI: Conclusion 10.1080/00365549850161098.

The diagnosis of CMV infection in Ogilvie's syndrome patients Ljungman P, Griffiths P, Paya C (2002). Definitions of without an evident etiological cause may be more frequent than cytomegalovirus infection and disease in transplant recipients. usually thought and must be considered earlier as possible in Clinical Infectious Diseases 34:1094-1097. order to start the appropriate treatment to avoid the serious complications that may appear in an episode of acute colonic

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