Cytomegalovirus Colitis in a Critically Ill Patient

527

□ CASE REPORT □

Cytomegalovirus Colitis in a Critically Ill Patient FollowingSevere Legionella Pneumonia with Multiple Organ Failure

Kei Nakashima 1, Masahiro Aoshima 1, Fumi Suzuki 1, Junko Watanabe 1 and Yoshihito Otsuka 2

Abstract

A 68-year-old man visited an emergency department complaining of dyspnea. He was diagnosed to have

Legionella pneumonia with multiple organ failure. Although his multiple organ failure improved, he suffered

from persistent abdominal pain and diarrhea with continuous minor bleeding. Colonoscopy revealed a longi-

tudinal ulcer of the rectum, below the peritoneal reflection. He was diagnosed with cytomegalovirus (CMV)

colitis. Antiviral therapy with ganciclovir was initiated. He finally underwent a colostomy after a bowel stric-

ture caused an intestinal outlet obstruction, which made oral intake impossible. Based on the present case, we

believe that CMV colitis must be considered as one of the differential diagnoses when critically ill patients

develop continuous diarrhea and abdominal pain.

Key words: cytomegalovirus colitis, critically ill patient, Legionella pneumonia, cytomegalovirus antigenemia

(Intern Med 55: 527-531, 2016)(DOI: 10.2169/internalmedicine.55.4857)

Introduction

Cytomegalovirus (CMV) infection is an important cause

of morbidity and mortality among patients with immunosup-

pression due to organ transplantation, malignant hematologic

disease or acquired immune deficiency syndrome

(AIDS) (1). The manifestations of CMV infection in im-

munosuppressed patients range from asymptomatic viral

colonization to severe organ disease. Patients without human

immunodeficiency virus (HIV) infection and those who are

not taking immunosuppressive drugs are not usually consid-

ered to be immunocompromised, and are therefore not con-

sidered to be at a high risk for CMV infection.

However, some authors have reported that the reactivation

of CMV is common in critically ill immunocompetent pa-

tients and that the reactivation is associated with prolonged

hospitalization and death (2). CMV infection or reactivation

is determined by either the isolation of CMV by viral cul-

ture, the detection of CMV proteins (pp65) through anti-

genemia, or the detection of DNA by a polymerase chain re-

action (PCR) using blood or other clinical samples. An in-

crease in the levels of CMV antigenemia during the follow-

up period is associated with an increased risk of CMV dis-

ease and death (3). The real-time PCR detection of CMV re-

activation has been shown to be independently associated

with continued hospitalization or death within 30 days after

intensive care unit (ICU) admission (4).

Nevertheless, CMV colitis is rarely recognized in ICU pa-

tients (5, 6). The diagnosis of CMV colitis might be compli-

cated as it may mimic the symptoms of other diseases (7).

The reported colonoscopic findings of CMV colitis include

various lesions such as a solitary ulcer, multiple ulcers,

ischemic colitis, polypoid lesions, and pseudomembranous

colitis-associated lesions (8-12). When investigations into

the etiology of acute hemorrhagic rectal ulcers are per-

formed, physicians should exclude other diseases such as

CMV colitis (13, 14). The definitive diagnosis of CMV coli-

tis is made based on the histological finding of inclusion

bodies in enlarged cells of the mucosa and by CMV-specific

immunohistochemical staining (6). However, CMV immuno-

histochemical staining is not routinely performed for pa-

tients with mucosal ulcers in which there is no obvious evi-

dence of inclusion bodies in large cells (14). Therefore, it is

a great challenge for intensivists and physicians to diagnose

CMV colitis in ICU patients in the clinical setting. CMV

colitis tends to occur in patients whose ICU stay is pro-

longed. This mostly includes patients with chronic kidney

１Department of Pulmonary Medicine, Kameda Medical Center, Japan and ２Department of Laboratory Medicine, Kameda Medical Center, Japan

Received for publication January 6, 2015; Accepted for publication May 19, 2015

Correspondence to Dr. Kei Nakashima, [email protected]

Intern Med 55: 527-531, 2016 DOI: 10.2169/internalmedicine.55.4857

528

Figure　1.　A chest X-ray showing air space consolidation mainly in the left upper lung field.

Table.　Laboratory Data on Admission and 46 Days after Admission.

On admission On 46 days after admissionHematology BiochemistryWBC 12,000 / L TP 6.6 g/dL CMV-Ag (C10/C11) (+)Neutro 95.0 % Alb 2.3 g/dL Slide 1: Positive cell 1Eosino 0.3 % AST 680 IU/L Slide 2: Positive cell 1Baso 0.0 % ALT 169 IU/L CMV IgG (+)Mono 0.9 % LDH 739 IU/L Index 65.0Lymph 3.8 % -GTP 597 IU/L CMV IgM (±)

RBC 384 g/dL T-bil 1.2 mg/dL Index 0.85Hb 13.1 g/dL CK 10,995 IU/L HIV antibody (-)Ht 37.5 % BUN 52 mg/dL WBC 4,500 / L

Blood coagulation Cre 2.81 mg/dL Neutro 51.4 %Plt 25.2×104 g/dL CK-MB 37 IU/L Lymph 35.9 %PT (INR) 1.29 Glu 125 mg/dL CD4 cell 666 / LAPTT 54 sec CRP 62.9 mg/dL IgG 1,480 mg/dL

BNP 88.5 pg/dL IgA 372.0 mg/dLMioglobin 34,000 ng/dL IgM 84.0 mg/dL

Blood atrial gas(reservoir mask O2 15L/min) Urinary antigen testpH 7.481 Legionella pneumophila (+)PaCO2 28.3 mmHg Streptococcus pneumoniae (-)PO2 62.7 mmHgHCO3

- 20.6 mmol/L Sputum cultureBE -1.7 mmol/L Legionella pneumophila (+)

Blood culture (-)

disease, end-stage renal disease, diabetes mellitus, or coro-

nary artery disease (14). Therefore, CMV colitis is not nec-

essarily limited to immunocompromised patients. The main

gastrointestinal manifestations of CMV colitis in intensive

care patients are intermittent bloody stool or massive lower

gastrointestinal bleeding and refractory watery diarrhea (14).

In a previous report, 2 of 18 such ICU patients died due to

CMV colitis, while 10 patients died of underlying disorders

that were not directly related to CMV colitis (14).

To the best of our knowledge, this is the first report of

CMV colitis in a critically ill patient following severe Le-gionella pneumonia with multiple organ failure.

Case Report

A 68-year-old man with a history of lacunar stroke, hy-

pertension and dyslipidemia visited an emergency depart-

ment complaining of dyspnea and fever. Laboratory tests

showed severe inflammation, rhabdomyolysis and acute re-

nal failure with severe hypoxemia (Table). Chest radiogra-

phy showed an infiltrative shadow, mainly in the left upper

lung (Fig. 1). He was intubated and was diagnosed with Le-gionella pneumonia based on the results of a urinary antigen

test. A combination antibiotic therapy with levofloxacin and

azithromycin was initiated to treat the Legionella infection.

Ceftriaxone was added to the antibiotic combination due to

the possible coincidence of other bacterial infections. We

chose the airway pressure release ventilation mode of the

respirator for managing acute respiratory failure. Noradrena-

line and vasopressin were administered to treat septic shock.

Renal dialysis was conducted to treat acute renal failure,

which arose from rhabdomyolysis. Since a drug eruption

was suspected after the first intravenous infusions of

levofloxacin, the drug was changed to rifampicin. He

showed severe liver dysfunction 2 days after admission, and

thus rifampicin and ceftriaxone were changed to ciproflox-

acin and ampicillin-sulbactam. The patient presented watery

diarrhea after the initiation of enteral tube feeding, although

Clostridium difficile tests for toxin A and B were negative.

He was extubated 13 days after admission, and received

non-invasive positive-pressure ventilation (NPPV) because

he showed hypercapnia. The patient’s respiratory failure im-

proved and he was weaned off NPPV; however, his abdomi-

nal pain and diarrhea with continuous minor bleeding per-

sisted. Computed tomography (CT) of the abdomen showed

wall thickening and the narrowing of the lumen of the sig-

moid colon, fluid collection in the oral side of the colon and

ascites (Fig. 2). A colonoscopy revealed longitudinal ulcers

covered with a uniform white mass from the rectum below

the peritoneal reflection to the portion 20 cm from the anal


529

Figure　2.　An abdominal CT scan showing wall thickening and the narrowed lumen of the sigmoid colon (arrow), fluid collection in the oral side of the colon and ascites.

Figure　3.　A colonoscopy revealed longitudinal ulcers cov-ered with a uniform white mass from the rectum below the peritoneal reflection to the portion 20 cm from the anal verge. The boundary around the ulcers were sharp and the surround-ing mucosa was mildly edematous and hemorrhagic.

Figure　4.　a: A histological study of the biopsy specimen showed the granulation of tissue with inflammatory cell infil-tration, and a small number of moderate to large cells with en-larged cell nuclei (arrow) (Hematoxylin and Eosin staining, ×400). b: An immunohistochemistry staining of some of the cells with enlarged nuclei was positive for CMV (arrow) (CMV pp65, ×400).

aa

bb

verge (Fig. 3). The boundary around the ulcers was sharp

and the surrounding mucosa was mildly edematous and

hemorrhagic. On the oral side, multiple ulcers were recog-

nized around the entire circumference, up to 20 to 25 cm

from the anal verge. Observation beyond 25 cm from the

anal verge was impossible because of the stool and hemor-

rhagic ulcers. These findings suggested the possibility of

collagenous colitis, ischemic colitis, ulcerative colitis or

CMV colitis. A histological examination of the biopsy speci-

men showed the granulation of tissue with inflammatory cell

infiltration, and a small number of moderate-to-large cells

with enlarged cell nuclei (Fig. 4a). An immunohistochemical

staining of some of the cells with enlarged nuclei was posi-

tive for CMV (Fig. 4b). The laboratory data indicated that

the patient was negative for HIV antibody and positive for

CMV antigenemia (Table). The creatinine clearance esti-

mated by Cockcroft-Gault equation was 51 mL/min at that

time. Thus we administered 150 mg of ganciclovir by infu-

sion every 12 hours for 6 weeks. The patient developed ab-

dominal pain and vomiting and underwent a second colono-

scopy, which revealed a large-bowel stricture at the rectum

above the peritoneal reflection. An ileus tube was indwelled

through his nose to reduce the pressure in the bowel. A third

endoscopic study performed 21 days after the second study

showed that, although the ulcer from the CMV colitis had

improved, a cicatricial stenosis of the colon had developed.

The patient finally underwent colostomy because the bowel

stricture caused intestinal outlet obstruction which made oral

intake impossible. The patient was discharged from hospital

126 days after admission, after he successfully resumed oral

intake. He has remained well throughout the follow-up pe-

riod.

Discussion

Human CMV belongs to the family Herpesviridae, which

has a seroprevalence of 40-100% in adults (15). Primary in-

fection in immunocompetent hosts seldom results in serious

disease and often goes unnoticed, sometimes causing a

mononucleosis syndrome resembling primary Epstein-Barr

virus infection (1). After the initial infection, the virus re-

mains in a latent state within the host, but can be reactivated

and has the potential to affect most organs. It is well recog-

nized that CMV reactivation causes diseases in severely im-

munosuppressed patients, most notably patients with HIV


530

infection, and those who have undergone solid organ or

bone marrow transplantation (1).

Clinically significant CMV-related diseases among im-

munocompetent hosts are uncommon. However, CMV reac-

tivation is a common occurrence in critically ill patients who

are apparently immunocompetent (2, 16). Small observa-

tional studies and a systematic review have suggested that

CMV reactivation in such patients is linked to an increased

length of hospitalization and/or ICU stay (2, 16, 17), an in-

creased duration of mechanical ventilation (2, 16), transfu-

sion (5), corticosteroid use (18) and severe sepsis (17). The

studies also suggest that CMV reactivation is associated

with high disease severity, and mortality (16, 17). Our pa-

tient developed severe Legionella pneumonia with multiple

organ failure, and with the exception of corticosteroid use,

he had most of the factors that have been linked to CMV re-

activation.

CMV has a comparatively long replication cycle. It en-

codes for a wide variety of gene products, playing an immu-

nomodulatory role in the host. The genome of CMV codes

sequentially for three genes, which encode for the

immediate-early (IE), early, and late proteins. The activation

of the IE region appears to be the first important step for the

reactivation of CMV. The IE enhancer/promoter sequences

contain various nuclear factor kappa B (NF-κB) consensus

sequences, which are regularly inactive (19). Therefore, any

mediator that activates NF-κB can trigger the reactivation of

CMV. Multiple stimuli are able to activate NF-κB, which

can in turn activate CMV. These include proinflammatory

cytokines, inflammatory enzymes, chemokines, and recep-

tors that are released in sepsis, burns, surgery, trauma, and

multiple organ failure syndrome (19, 20). CMV lies latent in

monocytes in which no viral gene is expressed. When these

monocytes differentiate into macrophages, as occurs during

inflammatory situations such as sepsis, burns, trauma or sur-

gery, the viral genes are expressed and viral replication

starts (19, 20). Thus, in patients who are critically ill as a

result of sepsis, trauma, burns or other conditions, CMV

may be reactivated through the immune mechanisms. Ac-

cording to this hypothesis, the likely cause of the onset of

the CMV colitis in our patient would have been severe sep-

sis and multiple organ failure rather than his Legionellapneumonia infection.

Although the gastrointestinal involvement of CMV is rare

in immunocompetent hosts, it is associated with significant

morbidity and mortality (21). Colitis has mainly been re-

ported, but CMV has also been implicated as a cause of

symptomatic esophagitis (22), gastritis (23) and ileitis (24)

in patients without underlying immunosuppression. While

most cases of CMV colitis are secondary to the reactivation

of latent infection in immunocompromised patients (7),

CMV colitis can occur as a primary infection in immuno-

competent patients. That our patient was positive for CMV

IgG, indicates that his CMV infection must have been a sec-

ondary infection (and not the primary infection), and that re-

activation occurred due to his critically ill status. In previous

reports, the overall mortality associated with CMV colitis in

immunocompetent patients has ranged from 26.7% to

31.8% (25, 26). Patients who are younger than 55 years of

age, and who have no other comorbidities tend to show a

good prognosis, with a significant rate of spontaneous reso-

lution. In contrast, older age and the existence of comorbidi-

ties tend to be associated with poor outcomes (25). The effi-

cacy of antibiotic therapy was unknown, although these re-

ports indicated that antiviral therapy was administered to 34-

53.3% of patients (25, 26). Antiviral therapy was initiated in

our patient after he developed persistent abdominal pain and

diarrhea with continuous bleeding and showed no sign of

spontaneous remission.

CMV colitis has not commonly been seen among the ICU

patients (5, 6). CMV colitis tends to occur in patients whose

ICU stay is prolonged; mostly patients with chronic kidney

disease, end-stage renal disease, diabetes mellitus, or coro-

nary artery disease (14). With the exception of a prolonged

ICU stay, our patient had none of the other above-mentioned

factors. The main gastrointestinal manifestations of CMV

colitis in ICU patients are intermittent bloody stool or mas-

sive lower gastrointestinal bleeding and refractory watery di-

arrhea (14). Thus the diagnosis of CMV colitis might be

complicated as it may mimic the symptoms of other dis-

eases. CMV colitis can be confused with ischemic colitis

when an elderly patient presents with bloody diarrhea and

abdominal pain (11). In our patient, other types of colitis

(such as ischemic colitis, collagenous colitis or ulcerative

colitis) were also suspected. The colonoscopic findings of

CMV colitis are various and include various lesions, such as

a solitary ulcer, multiple ulcers, ischemic colitis, polypoid

lesions, pseudomembranous colitis-associated lesions and

rectal ulcer (8-13). A previous case report described an ul-

cerated stricture caused by CMV colitis (27). Our patient

showed multiple longitudinal ulcers, which resulted in a

bowel stricture after the ulcers healed. The presence of ab-

normal mucosal surfaces prior to CMV infection may in-

crease the risk of this infection. This is demonstrated by evi-

dence of gastrointestinal CMV in patients with preexisting

inflammatory bowel disease (28). It is unclear whether our

patient had preceding colon diseases, but the existence of a

preceding bowel disease, such as ischemic rectal ulcer, is

possible because such diseases sometimes occur in critically

ill patients.

The detection of CMV antigenemia or serum CMV DNA

by PCR alone is insufficient for a diagnosis of CMV organ

disease. Histological evidence is also required. CMV colitis

can be histopathologically diagnosed by a biopsy of the co-

lon mucosa. Immunohistochemical staining with CMV

monoclonal antibodies on biopsy specimens raises the sensi-

tivity for the definitive diagnosis of CMV disease (6). In the

diagnosis of an ICU patient with bloody stool, positive

CMV-PCR results in blood or fecal samples are indirect evi-

dence of CMV colitis, and should encourage intensivists and

physicians to ask a pathologist to perform an immunohisto-

chemical staining for CMV using a biopsy specimen (14).


531

In the recent studies, the detection of CMV by real-time

PCR in stool samples was a reliable assay for the non-

invasive diagnosis of CMV colitis (29, 30). Since the gen-

eral status of our patient was relatively stable when he

showed the persistent clinical symptoms of colitis, he was

able to undergo a colonoscopy and the endoscopic findings

showed the possibility of CMV colitis, resulting in a defini-

tive diagnosis. If colonoscopy is not feasible in unstable

critically ill patients, the detection of CMV in stool samples

by a PCR might be helpful as a non-invasive diagnostic

method (30).

In conclusion, we believe that CMV colitis must be con-

sidered as one of the differential diagnoses when critically

ill patients develop continuous diarrhea and abdominal pain.

The authors state that they have no Conflict of Interest (COI).

AcknowledgementWe are grateful for the diligent and thorough critical reading

of our manuscript by Yoshihiro Ohkuni (Department of Pulmo-

nary Medicine) and John Wocher (Executive Vice President and

Director, International Affairs/International Patient Services, Ka-

meda Medical Center).

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Cytomegalovirus Colitis in a Critically Ill Patient