International Journal of Infectious Diseases 17 (2013) e348–e351

Case Report

Cytomegalovirus reactivation and colitis after left ventricular assist deviceplacement

Uriel Sandkovsky a,*, Diana F. Florescu a,b, John Y. Um c, Eugenia Raichlin d, Brian D. Lowes d,Matthew Kapalis d, Alexander Hewlett e, Kim F. Duncan c, Timothy Ryan c, Dominick DiMaio f,Whitney Wedel f, Andre C. Kalil a

a Division of Infectious Diseases, University of Nebraska Medical Center, Omaha, NE, USAb Division of Transplant Surgery, University of Nebraska Medical Center, Omaha, Nebraska, USAc Division of Cardiothoracic Surgery, University of Nebraska Medical Center, Omaha, Nebraska, USAd Division of Cardiology, University of Nebraska Medical Center, Omaha, Nebraska, USAe Division of Gastroenterology, University of Nebraska Medical Center, Omaha, Nebraska, USAf Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, Nebraska, USA

A R T I C L E I N F O

Article history:

Received 3 August 2012

Received in revised form 21 November 2012

Accepted 25 November 2012

Corresponding Editor: Mark Holodniy,

California, USA

Keywords:

Cytomegalovirus

Cytomegalovirus reactivation

Left ventricular assist device

Gastrointestinal bleeding

S U M M A R Y

We describe two patients who developed gastrointestinal bleeding due to cytomegalovirus (CMV) colitis

after placement of a HeartMate II left ventricular assist device (LVAD). We aim to raise awareness of CMV

colitis as a possible cause of gastrointestinal bleeding after LVAD placement and discuss potential

mechanisms for CMV reactivation and areas for future research.

� 2013 International Society for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

Contents lists available at SciVerse ScienceDirect

International Journal of Infectious Diseases

jou r nal h o mep ag e: w ww .e lsev ier . co m / loc ate / i j id

1. Introduction

Cytomegalovirus (CMV) is one of the most common viralpathogens, with established latent infection in humans and anestimated seroprevalence of 60–70% in the general population.1

CMV has long been recognized as the most common opportunisticinfection in immunocompromised patients, with accumulatingevidence of CMV reactivation in up to 36% of critically illnon-immunosuppressed patients.2 Risk factors for CMV reactiva-tion in these patients include: male gender, positive CMV IgG,enteral feeding, prolonged intensive care unit (ICU) stay, bloodtransfusions during ICU stay, severe sepsis or septic shock, andhigh acute physiology and chronic health evaluation (APACHE II)scores.2,3

Left ventricular assist devices (LVADs) have become a frequentalternative for patients with end-stage systolic heart failureas a bridge to heart transplantation or destination therapy.

* Corresponding author. Tel.: +1 402 559 8664; fax: +1 402 553 5527.

E-mail addresses: usandkovsky@unmc.edu, urielsanko@yahoo.com

(U. Sandkovsky).

1201-9712/$36.00 – see front matter � 2013 International Society for Infectious Disea

http://dx.doi.org/10.1016/j.ijid.2012.11.029

Complications after LVAD placement include pump failure, stroke,bleeding, infections involving the pump, driveline, or pocket,thrombosis, and renal failure.4 LVAD recipients may have severalrisk factors to reactivate CMV. A literature search showed threereports of CMV-related lower gastrointestinal (GI) tract diseasewith different devices (Table 1).5–7 We present the first two casesof CMV colitis that occurred in patients who underwent Heart-Mate II (HM-II) LVAD placement and discuss possible pathophys-iological mechanisms for CMV reactivation.

2. Case reports

2.1. Case 1

A 64-year-old man with ischemic cardiomyopathy, end-stageheart failure, and gout, who had required multiple previouscourses of steroids despite allopurinol maintenance, underwentplacement of an HM-II LVAD. He required 5 days of oraldexamethasone 4 mg a day for acute gout exacerbation 12 daysafter surgery. Three days later, he developed hematochezia and hishemoglobin dropped to 10.3 g/dl, requiring transfusion of 2 unitsof irradiated red blood cells. Colonoscopy showed a friable cecal

ses. Published by Elsevier Ltd. All rights reserved.

Table 1Cases of CMV reactivation in the lower gastrointestinal tract after LVAD

Reference Device Risk factors Clinical presentation Labs/cultures; pathology/cultures Management/outcome

Aleksic et al.5 HeartMate 10001

(pulsatile)

Critical illness, ICU,

prolonged hospital stay,

unclear CMV serostatus

Persistent GI bleeding;

ileitis/enteritis, 27 days

post-LVAD

No initial serology or PCR;

pathology showed ileitis and

positive CMV stains

Ileal resection, 14 days

ganciclovir followed by

acyclovir for 3 months

Huttner et al.6 Incor1 (axial flow) Male, critical illness, ICU,

prolonged hospital stay,

CMV IgG-positive

Pneumonitis and ileitis,

53 days post-LVAD

Positive CMV PCR from pleural

fluid; negative cultures (blood

and lung); pathology: lung

showed necrotizing pneumonia,

inclusion bodies and positive

CMV stains and ileitis with

positive CMV stains

Death

Pfau and Rothstein7 Unspecified Male, critical illness, ICU,

prolonged hospital stay,

positive CMV IgG

Lower GI bleeding;

cecal ulcer

Biopsy of cecal ulcer with acute

inflammatory exudate and

intranuclear inclusion

Ganciclovir � 21 days,

no recurrence

Sandkovsky et al. HeartMate II1

(axial flow)

Male, steroids, positive

CMV IgG

Patient 1: lower GI

bleeding, necrosis of

the cecum

Blood CMV PCR-negative; no

cultures; pathology: mucosal

ulceration, distorted architecture,

acute and chronic inflammation;

CMV stains positive

Right hemicolectomy

and ganciclovir � 28

days; no recurrence

HeartMate II1

(axial flow)

Male, enteral feeding,

blood transfusions,

positive CMV IgG

Patient 2: lower GI

bleeding, proctocolitis

Blood CMV PCR 770 copies/ml;

acute and chronic inflammation

of the rectosigmoid colon and

ileocecal valve; CMV stains positive

Right hemicolectomy and

ganciclovir � 28 days;

no recurrence

CMV, cytomegalovirus; ICU, intensive care unit; IgG, immunoglobulin G; GI, gastrointestinal; LVAD, left ventricular assist device; PCR, polymerase chain reaction.

Figure 1. (a) Ulcerated mucosal surface of the colon containing stromal cells with

eosinophilic intra-nuclear inclusions (black arrow) giving an ‘owl’s eye’ appearance

consistent with cytomegalovirus (CMV) infection (hematoxylin and eosin, 400�).

(b) Immunoperoxidase staining for CMV demonstrated the presence of numerous

infected cells within the ulcerated mucosal surface of the colon (200�).

U. Sandkovsky et al. / International Journal of Infectious Diseases 17 (2013) e348–e351 e349

mucosa, ulcerations, and granulation tissue suggestive of ischemiccolitis. Failure of medical therapy prompted surgical interventionwith a right hemicolectomy 3 days later. Histopathology revealedan ulcerated colonic mucosa, distorted architecture, and acuteand chronic inflammation. Immunohistochemistry staining waspositive for CMV, and viral inclusions were seen in retrospectwith hematoxylin and eosin stain (Figure 1). CMV by PCR inblood was negative. Previous CMV IgG was positive. He received a14-day induction therapy with intravenous ganciclovir 5 mg/kgevery 12 h for 10 days and valganciclovir 900 mg twice dailyfor 4 days; then valganciclovir was changed to 450 mg dailyto complete 28 days of maintenance therapy. No recurrenceof CMV colitis or lower GI bleeding was seen after 8 months offollow-up.

2.2. Case 2

A 71-year-old man with non-ischemic dilated cardiomyopathyand end-stage heart failure underwent HM-II LVAD placement,aortic valve repair, and tricuspid valve annuloplasty. His coursewas complicated by respiratory failure, shock, ischemic hepatitis,renal failure, and hemorrhagic cystitis, requiring mechanicalventilation, vasopressor support, and hemodialysis. He developedlower GI bleeding that required multiple red blood cell transfu-sions. A lower endoscopy showed ulceration of the ileocecal valve,transverse colon, and a 10 mm ulcer in the recto-sigmoid colon.Because of persistent bleeding and the need to anticoagulate forLVAD, a right hemicolectomy was performed on post-operativeday 32. Histopathology from the endoscopy and the resectedhemicolon specimens showed an acute inflammatory infiltrate ofthe recto-sigmoid and ileocecal valve, with ulceration andpositive immunohistochemistry staining for CMV; in retrospecthematoxylin and eosin stain showed cells with possible viralinclusions (Figure 2); stains for other pathogens (fungal and acid-fast bacilli) were negative. Blood CMV by PCR was 770 copies/ml.The patient’s CMV IgG was positive previous to LVAD placement.He received a 14-day induction with intravenous ganciclovir5 mg/kg per day (350 mg a day adjusted to kidney function), thenswitched to oral valganciclovir 450 mg daily for 28 daysmaintenance therapy. He has not had recurrent bleeding episodesafter 6 months.

Figure 2. (a) Ulcerated mucosal surface of the colon containing stromal cells with eosinophilic intra-nuclear inclusions (black arrow) consistent with cytomegalovirus (CMV)

infection (hematoxylin and eosin, 400�). (b) Immunoperoxidase staining for CMV demonstrated the presence of multiple infected cells within the ulcerated mucosal surface

of the colon (200�).

U. Sandkovsky et al. / International Journal of Infectious Diseases 17 (2013) e348–e351e350

3. Discussion

Here we underscore a potentially important infectious compli-cation in LVAD recipients. Complications after LVAD placement arecommon4 and GI bleeding is one of the most common and well-described complications, occurring in a fifth of patients.4,8–10

Interestingly, there has been a significant increase in GI bleedingepisodes related to HM-II LVAD compared to HM-I LVADplacement.8 The lower GI tract is most commonly affected, andmost series have been retrospective and have not includedhistopathology descriptions.9,10 Excluding ischemia, at least twopathophysiological mechanisms may explain the increase in GIbleeding: first the formation of angiodysplasias in the small bowel,a similar mechanism to the one described in the setting of aorticstenosis; and second, the development of acquired von Willebranddisease type 2A, which is most likely caused by shear stress on redblood cells flowing through the LVAD pump.8–10 We conjecturethat CMV reactivation in the lower GI tract, especially in theterminal ileum or colon, may be another potential cause ofbleeding. In fact, there are data to support more severe colitis andbleeding in mice with latent murine CMV infection in the gut.11 Onthe other hand, CMV reactivation is well described in patients withinflammatory bowel disease, so it is possible that viral reactivationin our patients might have occurred in a similar fashion.12,13

It may be worth exploring if LVAD recipients reactivate CMV at asimilar rate to critically ill non-immunosuppressed patients. CMVreactivation may be self-limited and resolve after a few weeks, but itis worth considering given its association with increased all-causemortality, prolonged ventilator support, and high rates of nosoco-mial infections.2,3 A summary of the previously reported cases in the

literature with a comparison to our cases is provided in Table 1.5–7

The underlying mechanism of CMV reactivation in critically illpatients is probably related to dysfunction of the cellular immunesystem, with shifting of Th1 to Th2 responses, or even immuneparalysis.2,3 Data suggest that LVAD placement may lead to immunedysfunction. One proposed mechanism is through lymphopeniaafter LVAD implantation, with selective loss of Th1 cytokine-producing CD4 lymphocytes through apoptosis and concomitantactivation of Th2 CD4 T-cells and B-cell hyper-reactivity.14–16

One of the limitations of our report is the scarce literature onCMV reactivation in patients undergoing LVAD implantation.However, we raise several important questions, including poten-tial areas for future research: (1) Is it worth looking for CMVreactivation in patients who undergo LVAD placement? If so, whenwould be the best time to look? If we hypothesize that CMVreactivation in LVAD recipients is as common as in non-immunosuppressed patients admitted to the ICU, susceptibilityto CMV reactivation should be higher in the early period afterdevice placement while patients are in the ICU, receive bloodtransfusions, undergo multiple procedures, or have APACHE scores>20.2 (2) Should we monitor CMV viremia in every patient, justselected patients, or do no monitoring at all? How often should wemonitor and what would be the cost associated with CMV by PCR,which may range between US$ 120 and 150, depending on thecenter. (3) Because gastrointestinal bleeding is a commoncomplication we could easily be overlooking many cases of CMVcolitis. Since most patients would undergo a colonoscopy toexplore the source of bleeding, looking for CMV would not be adifficult task. Direct visualization would be key to obtainingbiopsies of suspicious tissue or ulcers for proper histopathological

U. Sandkovsky et al. / International Journal of Infectious Diseases 17 (2013) e348–e351 e351

analysis. On the other hand, would it be useful to look for CMV inpatients who are CMV IgG-negative? (4) Which non-immunosup-pressed patients with CMV reactivation need treatment? It is likelythat there will be agreement to treat patients with establishedcolitis, but what about patients with transient CMV viremia? Whatviral load threshold should we look at since end-organ disease likecolitis may either present with low-level or even absence ofviremia, as was the case in our patients. Should high-risk patientsreceive prophylaxis? Ultimately, we have to consider that theindiscriminate treatment of CMV would expose patients topotentially toxic medications with substantial side effects, notto mention the high cost of antiviral therapy.

We believe that this is an area definitely worth exploring. Awell-designed multicenter prospective cohort study could help usto understand whether and how often CMV reactivation anddisease occurs in patients who undergo LVAD implantation.

Acknowledgements

We thank the participating patients and their families.Conflict of interest: Uriel Sandkovsky, John Um, Brian Lowes,

Matthew Kapalis, Alexander Hewlett, Kim Duncan, Timothy Ryan,and Andre Kalil report no conflict of interest. Diana F. Florescureports being a Grant Investigator for Chimerix and ScientificAdvisor for Behring.

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