MAJOR ARTICLE
Evaluation of Anatomic Changes in Young Children
with Natural Rotavirus Infection: Is Intussusception
Biologically Plausible?
Christine G. Robinson, Marta Hernanz-Schulman, Yuwei Zhu, Marie R. Griffin, William Gruber,
and Kathryn M. Edwards
Pediatric Clinical Research Office, Nashville, Tennessee
Background. Several studies have shown an association between vaccination with the rotavirus vaccine and
the development of intussusception. We evaluated the plausibility of a causal association between natural rotavirus
infection and intussusception.
Methods. We performed ultrasound measurements, in infants with confirmed rotavirus infection and in healthy
control subjects, of the ileum wall thickness and mesenteric lymph nodes, at enrollment and 1 month later.
Results. Thirteen pairs of patients with rotavirus infection and control subjects were enrolled. The mean distal
ileum wall thickness at the first examination was 3.0 mm in patients with rotavirus infection and 2.0 mm in
control subjects (P p .037). The maximum lymph node size in patients with rotavirus infection was 11.6 mm at
the first examination and 7.4 mm at the second examination (P p .017 ). Nodal aggregates and free fluid were also
observed more commonly among patients with rotavirus infection (54% vs. 9%; P p .033 for both).
Conclusion. Rotavirus infection was associated with increased distal ileum wall thickness and lymphadenopathy
during the illness period. These changes suggest a plausible mechanism by which rotavirus infection could cause
intussusception.
Rotavirus is a common cause of gastrointestinal illness
in young children. Peak illness rates occur in children
aged 4–23 months. By age 5 years, nearly all children
test seropositive for rotavirus, which indicates previous
infection with this ubiquitous virus. Annually, rotavirus
infections cause 800,000 deaths worldwide and cost the
US economy an estimated $250 million in hospitalization costs [1].
At least 6 different rotavirus vaccine strains that use
rhesus, bovine, recombinant human and rhesus, and human infectious strains have been developed. One strain,
rhesus-human reassortant tetravalent vaccine (RRV-TV;
Wyeth-Ayerst), was withdrawn from the market after a
reported increase in the incidence of intussusception in
Received 14 May 2003; accepted 15 September 2003; electronically published
2 April 2004.
Financial support: Wyeth Lederle Vaccines and Pediatrics (unrestricted educational
grant).
Correspondence: Dr. Kathryn M. Edwards, Pediatric Clinical Research Office, CCC5323 Medical Center North, Nashville, TN 37232 ([email protected]).
No reprints will be provided.
The Journal of Infectious Diseases 2004; 189:1382–7
2004 by the Infectious Diseases Society of America. All rights reserved.
0022-1899/2004/18908-0007$15.00
1382 • JID 2004:189 (15 April) • Robinson et al.
the vaccine recipients [2]. Recent commentaries have
discussed the hypothesis that RRV-TV is associated with
intussusception during the immediate postimmunization
period but protects against intussusception that occurs
after subsequent infection with wild-type rotavirus [3,
4]. This hypothesis gains credibility if biological plausibility can be established whereby natural rotavirus infections could lead to intussusception.
Intussusception is the most common cause of intestinal obstruction in young children [5]. Although it is
believed to be associated with hypertrophy of Peyer
patches and mesenteric lymphadenopathy, intussusception in this age group is idiopathic in the vast majority
of cases. The results of virus studies have indicated that
∼50% of children with intussusception shed virus in
stool, with adenovirus, enterovirus, and cytomegalovirus being the most commonly implicated viruses [6–
11]. Before the experience with RRV-TV vaccine, natural rotavirus infection had not been shown to be definitively associated with intussusception. However, few
researchers had attempted to identify rotavirus using
rotavirus-antigen detection or virus-isolation procedures. Of note, a comprehensive review of previously
published data by Rennels et al. [6] in 1998 concluded
that the 3 small case series that reported the identification of
rotavirus infection in children with intussusception constituted
insufficient evidence to conclude that the infection caused intussusception. These case series lacked control subjects and
predated the development of rotavirus-antigen detection procedures and culture methods.
The purpose of our pilot study was to explore possible mechanisms by which natural rotavirus infection might cause intussusception by using ultrasound to define bowel-wall thickening and mesenteric lymphadenopathy in rotavirus-infected
patients and in healthy age- and sex-matched control subjects.
Ultrasound offers an ideal method to evaluate alterations in the
bowel and mesentery that might be induced by a variety of disease
processes. It is also highly sensitive in detecting intussusception
[5] and has been used to measure bowel-wall thickness in a
variety of disorders, including inflammatory bowel disease, cystic
fibrosis, and Yersinia and Salmonella infection [12, 13].
SUBJECTS AND METHODS
Study design and population. This was a prospective matchedcohort study that enrolled children aged 0–13 months. Children
with symptomatic rotavirus infection were identified in a variety
of clinic, emergency department, and inpatient care settings.
Asymptomatic, healthy control children were identified contemporaneously at 3 general pediatric clinics in the area during wellchild visits. They were matched, by age and sex, to existing patients with rotavirus infection and had no gastrointestinal
symptoms at the time of enrollment. Children considered for
either group who had a preexisting medical condition affecting
the bowel—such as cystic fibrosis, inflammatory bowel disease,
or prior gastrointestinal surgical procedures—were ineligible for
the study. Informed consent was obtained from the parents or
guardians of all subjects and control subjects. The study was
approved by Vanderbilt University’s institutional review board.
Data collection. At enrollment, each subject’s parent or
guardian was interviewed, to obtain demographic data, the extent and duration of gastrointestinal symptoms (if the children
had rotavirus infection), and general contact information. All
subjects also submitted a stool sample at enrollment to be tested
for the presence of rotavirus antigen and other intestinal viruses. Rotavirus status was verified in all study enrollees using
stool samples tested with either Rotaclone or Immuno-Rotastat
cards (Meridian Bioscience), both at enrollment and at the
follow-up visit 1 month later. The enrollment and follow-up
stool samples were also tested for the presence of anti–rotavirus
IgA and were cultured for common gastrointestinal viruses (adenovirus, enterovirus, and rotavirus). Patient follow-up ended
at the time of the second ultrasound examination, 1 month
after enrollment.
All subjects underwent ultrasound examination performed
by a single board- and Certificate of Added Qualification–certified pediatric radiologist blinded to the rotavirus infection
status of the patients. Ultrasound examinations were performed
at enrollment and 1 month later at the follow-up visit. The
examination was done using ATL 5000 equipment (Bothell) or
Sequoia (Acuson), with a linear transducer operating at a variable frequency of 7.5–12 MHz. The examinations were performed with graded compression, beginning at the inferior surface of the liver and identifying the ascending portion of the
colon and the small-bowel loops in the right abdomen and
right lower quadrant. The terminal ileum (TI) was considered
to have been identified only if it was observed inserting into
the cecum via the ileocecal valve (figure 1). A distended diameter was defined as the noncompressed outer-wall-to-outerwall diameter of a loop of bowel (figure 2). Wall thickness was
defined as one-half of the outer-wall-to-outer-wall diameter of
a completely compressed loop (figure 3). Nodes (figure 4) and
nodal aggregates (figure 5) were identified and measured at the
longest axis (figure 4).
Because intussusception may begin in the distal ileum rather
than in the ileocecal valve area, other loops of bowel in the
distal right lower quadrant, in addition to the TI, were selected
and measured in the same manner. These were designated as
“distal ileum” loops; both the noncompressed diameter and
compressed wall thickness were measured in these areas and
recorded. Mesenteric lymph nodes, singly and in aggregate,
were measured when they were present. The presence of free
intraperitoneal fluid was also recorded.
The primary study end points were the measurement of the
diameter and wall thickness of the TI. The secondary study
Figure 1. Right lower quadrant compression image outlining the terminal ileum at the ileocecal valve of an 11-month-old patient with rotavirus infection. The distance between the calipers indicates the outerwall-to-outer-wall bowel diameter of the terminal ileum (1.19 cm). Single
wall thickness, 6 mm. Arrows outline the cecum clasping the terminal
ileum at the ileocecal valve.
Ultrasound Use in Rotavirus Infection • JID 2004:189 (15 April) • 1383
Figure 2. Right lower quadrant noncompression image outlining fluidfilled, distended loops of the bowel in a 7-month-old patient with rotavirus
infection. The distance between the calipers indicates the outer-wall-toouter-wall bowel diameter of the terminal ileum (1.35 cm). Note that
there is similar distension of adjoining loops (arrows) that contain more
echogenic fluid.
end points were the diameter and wall thickness of small-bowel
loops, lymph node size, and the presence and extent of aggregate lymph nodes. Group means were compared using the
Mann-Whitney U test, and comparisons between first and second ultrasound results were done using the Wilcoxon signed
rank test for each group. Group comparisons included the results of (1) the first examination of a patient with rotavirus
infection versus that of a control subject, (2) the second examination of a patient with rotavirus infection versus that of
a control subject, (3) the first versus the second examination
of a patient with rotavirus infection, and (4) the first versus
the second examination of a control subject. Categorical variables were compared using the x2 or Fisher’s exact test, as
appropriate. Missing data were excluded on an analysis-byanalysis basis. Data were analyzed using SPSS software.
contrast to 36% of patients with rotavirus infection. Of the
patients with rotavirus infection, 36% were evaluated in an emergency room setting and received intravenous (iv) rehydration
therapy, 43% were admitted as an inpatient to the hospital for
iv rehydration therapy, and 21% were seen in an outpatient clinic
and did not receive iv rehydration therapy. Symptoms in rotavirus-infected children were abdominal pain (71%); loose stools
(100%; mean, 17 stools/24 h); vomiting (86%; mean, 5.2 times/
24 h); signs of dehydration, such as sunken fontanel, reduced
tear production, and dry mucous membranes (57%); and prodrome of respiratory symptoms, including cough and/or coryza
(64%). None of these parameters was found to correlate statistically with the degree of bowel-wall thickening, bowel distension,
or lymphadenopathy.
One of our study patients, who was hospitalized for severe
rotavirus infection, had a transient ileocolic intussusception
that was imaged during the real-time ultrasound test (figure
6). This intussusception was initially 3 cm in length, reduced
to 1.4 cm, and then resolved without intervention. Clinically,
the patient did not develop further symptoms.
TI end points. In the first ultrasound examination, the TI
was visualized in 46% of patients with rotavirus infection and
in 62% of control subjects. At the second examination, 1 month
later, the TI was visualized in 64% of patients with rotavirus
infection and in 46% of control subjects. The mean TI diameter
(table 1) was 6.6 mm in patients with rotavirus infection and
5.9 mm in control subjects (P p .755). The TI wall thickness
was 3.4 mm in patients with rotavirus infection and 2.8 mm
in control subjects (P p .470). The mean TI diameter and wall
thickness did not change significantly between the first and
second examination in either patients with rotavirus infection
or control subjects.
Small-bowel end points. Distal ileum loops were visualized
in all study subjects. There were no significant differences in
RESULTS
Study population. We identified 14 children with rotavirus
infection and enrolled age- and sex-matched healthy control
subjects for 13 of them. A total of 13 pairs of subjects had both
first and second ultrasound examinations, which formed the
basis of the comparative analyses.
Clinical presentation. The average age at enrollment was
7.2 months for patients with rotavirus infection and 7.3 months
for control subjects, with an average time of 60 h from initial
enrollment and collection of stool sample to the completion
of the first ultrasound examination. A total of 57% of patients
with rotavirus infection were male, and 54% of control subjects
were male. None of the control subjects attended day care, in
1384 • JID 2004:189 (15 April) • Robinson et al.
Figure 3. Right lower quadrant compression image outlining normal
loops of bowel in a 12-month-old control subject. The distance between
the calipers indicates the outer-wall-to-outer-wall bowel diameter (5.5 mm).
Single wall thickness, 2.75 mm; P, transverse axis of the right psoas muscle.
Free fluid in the abdomen. Free fluid in the abdomen was
detected at the first ultrasound examination in 54% of patients
with rotavirus infection, compared with 23% of control subjects
(P p .107). At the second examination, free fluid was detected
in 9% of patients with rotavirus infection (P p .033 vs. the
first examination).
DISCUSSION
Figure 4. Right lower quadrant compression image outlining a single
lymph node, outlined by calipers, in a 6-month-old control subject. The
distance between the calipers is 1.2 cm.
distal ileum distention between patients with rotavirus infection
and control subjects at either examination, and no significant
change was seen in this measurement for patients with rotavirus
infection between the first and second examinations (table 1).
The mean small-bowel loop wall thickness was 3.0 mm in patients with rotavirus infection at the time of the first ultrasound,
versus 2.0 mm in control subjects (P p .037). Wall thickness
declined to 2.0 mm by the second examination in the patients
with rotavirus infection (P p .123 vs. the first examination).
Adenopathy. Nodes were visualized in 92% of patients
with rotavirus infection at the first examination and in 82% at
the second, whereas nodes were visualized in 62% of healthy
control subjects at the first examination and in 69% at the
second. Nodes were measured at the longest diameter (see table
1). Patients with rotavirus infection had a larger maximum
lymph node size at the first examination than did control subjects—at the first examination, the maximum lymph node size
in patients with rotavirus infection was 11.6 mm, compared
with 8.0 mm in control subjects (P p .057); this value decreased to 7.4 mm at the second examination (P p .017).
Patients with rotavirus infection more commonly had nodal
aggregates, compared with control subjects; at the first examination, aggregates were seen in 54% of patients with rotavirus
infection, compared with 15% of control subjects at the first
examination (P p .097). Nodal aggregates were also visualized
more frequently at the first examination than at the second,
with aggregates seen in only 9% of patients with rotavirus infection at the second examination (P p .033 ). The mean maximum diameter of lymph node aggregates at the first examination was 27.7 mm in patients with rotavirus infection,
compared with 22.0 mm in control subjects (P p .889 ). At the
second examination, the size of lymph node aggregates had
decreased to a maximum of 15.0 mm in patients with rotavirus
infection, compared with 21.0 mm in control subjects (P p
.667). P values for intragroup comparisons were incalculable,
because no patient had aggregates at both examinations.
We undertook this pilot study to define more clearly the effect
of natural rotavirus infection on bowel anatomy, with the purpose of exploring whether natural rotavirus infection–induced
changes might predispose patients toward intussusception. Our
results establish that rotavirus infection in young children affects
the bowel wall, most notably by increasing wall thickness in the
distal ileum and by enlarging mesenteric lymph node size. The
effect of rotavirus on the bowel wall is a possible mechanism for
virally induced intussusception, as has been postulated in studies of adenovirus and of intussusception [14–20]. These prior
studies documented the presence of adenovirus in the mesenteric lymph nodes of patients with intussusception, and 1
documented the presence of adenovirus in the appendiceal tissue within the bowel wall [24]. Our present findings show that
rotavirus similarly affects the bowel wall, but its role in inducing
intussusception remains unclear.
Much of the published data that have examined the role of
rotavirus in triggering intussusception predate current rotavirus
detection and culturing methods. Three case series that analyzed the role of rotavirus in triggering intussusception were
undertaken in the late 1970s and early 1980s and used electron
microscopy (EM), ELISA, or immunofluorescence to identify
rotavirus in stool samples from young children. The first study,
conducted by Konno et al. [8] in Japan, identified rotavirus in
Figure 5. Right lower quadrant compression image outlining lymph
nodes of a 5-month-old patient with rotavirus infection. The distance between the + crosshairs equals a single node diameter (8.3 mm); the distance
between the ⫻ crosshairs equals the aggregate diameter (3.6 cm).
Ultrasound Use in Rotavirus Infection • JID 2004:189 (15 April) • 1385
Figure 6. Right abdominal compression image illustrating incidental ileocecal intussusception occurring coincidentally at the time of imaging in a
4-month-old patient with rotavirus infection. Transverse (left) and longitudinal (right) images at the level of the hepatic flexure outline the diagnostic
bowel-within-bowel appearance. Arrowheads, intussusceptum; arrows, intussuscipiens; P, long axis of the psoas muscle.
11 of 30 patients (using EM) who presented with intussusception over an unstated time frame. Nine of the patients who
tested positive for rotavirus presented with intussusception during the winter months, the seasonal peak for rotavirus infections
in Japan [8]. In the same study, adenovirus was isolated in 9
of 30 patients, with no dual infections reported [8]. The second
study, which was conducted by Nicolas et al. [7] in France,
used ELISA to identify increases in rotavirus antibody titers in
6 (9%) of 64 patients with intussusception; 4 of these patients
also demonstrated serologic increases in hemagglutination inhibition titers to adenovirus, which suggested the possibility of
Table 1.
dual infection and resulted in 2 (3%) of 64 having rotavirus
infection alone. The third study, conducted by Mulcahy et al.
[9] in Australia, used EM, ELISA, and immunofluorescence of
fecal extracts to identify rotavirus infection. Two (2%) of 120
children with intussusception showed evidence of current or
recent rotavirus infection [9].
Are there varying degrees of intussusception, some of which
“stick” and require clinical or surgical management and others
that transiently resolve and do not require clinical attention?
By chance, we observed by ultrasound, during the present study,
a transient intussusception in a child with rotavirus infection
Characteristics of patients with rotavirus infection vs. control subjects, during 2 examinations.
Characteristic
visualized
TI, %
Control subjects,
examination
Patients with rotavirus,
examination
1
2
46
64
Within-group P
.444
1
2
62
46
Between-group P
for examination
Within-group P
1
2
.431
.691
.392
Distended
6.6 (2.7)
4.0 (2.4)
.109
5.9 (1.9)
5.4 (2.8)
1.000
.755
.818
Wall thickness
3.4 (1.5)
2.6 (1.4)
.109
2.8 (0.8)
2.7 (1.5)
.581
.470
1.000
Distal ileum, %
Distended
Wall thickness
Nodes, %
Maximum size
Nodal aggregates, %
Maximum size
Free fluid, %
1.000
1.000
1.000
10.4 (4.5)
100
4.6 (3.3)
.138
7.1 (4.7)
3.6 (2.1)
.115
.181
.285
3.0 (1.4)
2.1 (0.8)
.123
2.0 (1.1)
1.6 (0.3)
.673
.037
.080
1.000
.160
.649
.588
.057
.666
1.000
.097
1.000
.889
.667
.107
.458
92
100
1.000
82
.576
11.6 (4.2)
7.4 (2.1)
.017
54
9
.033
27.7 (12.3)
54
a
15 (… )
9
b
…
.033
100
62
8.0 (3.4)
15
22 (7.1)
23
100
69
6.9 (2.4)
15
21 (1.4)
0
…
b
.220
NOTE. Data are mean millimeters (SD), unless otherwise noted. The first examination was done at enrollment, and the second was done at the follow-up
visit 1 month later. All measurements were made using ATL 5000 or Acuson Sequoia ultrasound by a board- or Certificate of Added Qualification–certified pediatric
radiologist blinded to group assignment. Distal ileum measurements were taken from a representative loop of bowel in the right lower quadrant. Wall thickness
was defined as one-half of the outer-wall-to-outer-wall diameter of a completely compressed loop. The distended diameter was defined as the noncompressed
outer-wall-to-outer-wall diameter of a loop of bowel. Lymph nodes and lymph node aggregates were measured at their longest diameter. The Mann-Whitney U
test was used to make intergroup comparisons, and the Wilcoxon signed rank test was used to make intragroup comparisons. Categorical variables were
compared using the x2 or Fisher’s exact test, as appropriate. Missing data were excluded on a case-by-case basis. Values given in bold are statistically significant.
TI, terminal ilium.
a
b
No SD is given for this measure because only 1 value is represented.
No P value is given because no patient had nodal aggregates at both the first and second examinations.
1386 • JID 2004:189 (15 April) • Robinson et al.
(figure 6). Published data [14, 21] and anecdotal reports from
pediatric surgeons support the notion that the bowel tissue in
young children transiently telescopes without leading to clinical
intussusception. Our results suggest that this may occur in rotavirus infection. Enlarged mesenteric nodes and nodal aggregates
are often observed during the surgical correction of intussusception [14, 17, 19]. Konno et al. [22], using autopsy material,
reported that hyperplasia of the intestinal lymphoid tissue occurs
in acute gastroenteritis caused by rotavirus infection. Pathological
data on resected bowel from intussusceptions associated with the
now-withdrawn rotavirus vaccine identified lymphoid hyperplasia as possible lead points [23]. Furthermore, Berrebi et al. [24]
reported the isolation of adenovirus in resected appendiceal tissue
from children with acute intussusception. Thus, these findings
support a role for viral infections, specifically natural rotavirus
infection, in the creation of potential lead points for intussusception, as was observed in our study.
Although this was only a pilot study to evaluate the relationship
between rotavirus and intussusception, our findings are novel
and suggest that this association needs to be investigated further.
Ecological studies conducted in the United States have not suggested a link between rotavirus and intussusception [6]. However,
ecological approaches are not sensitive to strong associations that
occur very infrequently, as has been recently articulated [3]. The
prospective viral surveillance of children with intussusception
and control subjects that includes state-of-the art rotavirus detection and culture methods is the only way to definitively address
these relationships and is urgently needed.
Our study aimed to answer the question of whether there is
any relationship between rotavirus infection and bowel changes.
However, our study was not designed to answer the greater
question of the relationship between rotavirus infection and
intussusception. Our pilot study was limited by its small size,
the difficulty in positively identifying the TI in all patients
studied, and the wide variance in bowel measurements among
patients with rotavirus infection. This variance could have resulted from differences in the clinical severity of rotavirus infection or the time of presentation for clinical care.
An inherent difficulty in designing the study was ascertaining
what the “normal” bowel wall thickness and diameter are in
young children. Further complicating the design was the dearth
of prior scientific literature regarding viral causes of intussusception. To our knowledge, questions such as to what extent
the TI would need to thicken or distend to provoke an intussusception that requires clinical attention have not been addressed. Our findings point to a normal value of ∼2 mm for
wall thickness in the distal ileum and an uncompressed loop
diameter of 3.5–4 mm in the distal ileum. Further study is
needed to better define these “normal” values and to understand the role of rotavirus infection in intussusception.
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