cytomegalovirus colitis in a critically ill patient
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□ 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, kei.7.nakashima@gmail.com
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
Intern Med 55: 527-531, 2016 DOI: 10.2169/internalmedicine.55.4857
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
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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
Intern Med 55: 527-531, 2016 DOI: 10.2169/internalmedicine.55.4857
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).
Intern Med 55: 527-531, 2016 DOI: 10.2169/internalmedicine.55.4857
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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