Eur J Pediatr (2007) 166:241247

DOI 10.1007/s00431-006-0237-6

ORIGINAL PAPER

Rotavirus and not age determines gastroenteritis

severity in children: a hospital-based study
Fabio Albano & Eugenia Bruzzese & Antonino Bella &
Antonio Cascio & Lucina Titone & Serenella Arista &
Giancarlo Izzi & Raffaele Virdis & Paola Pecco &
Nicola Principi & Massimo Fontana & Alfredo Guarino

Received: 15 March 2006 / Revised: 16 June 2006 / Accepted: 26 June 2006 / Published online: 29 August 2006
# Springer-Verlag 2006

Abstract
Background The severity of childhood gastroenteritis is
generally believed to be age-related rather than aetiologyrelated. Rotavirus-induced gastroenteritis is more severe
than gastroenteritis caused by other enteric pathogens and is
also age-related. We thus addressed the question of whether
the increased severity of rotavirus-induced gastroenteritis is
related to age or to features intrinsic to the agent.
Study design In this multicentre, hospital-based, prospective survey, we evaluated the severity of diarrhoea in
rotavirus-positive and rotavirus-negative children up to
4 years of age. Severity was assessed with a score in four
groups of age-matched children.
Results Rotavirus was detected in 381 of 911 children.
Disease severity was evaluated in 589 cases for which
F. Albano : E. Bruzzese : A. Guarino (*)
Dipartimento di Pediatria, Universit di Napoli Federico II,
via S. Pansini 5,
80131 Naples, Italy
e-mail: alfguari@unina.it
A. Bella
Istituto Superiore di Sanit,
Rome, Italy

clinical data were complete. The rotavirus-positive and

rotavirus-negative groups differed with regards to diarrhoea
duration, hospital stay, degree of dehydration and the
number of episodes of vomiting. Gastroenteritis was more
severe in rotavirus-positive than in rotavirus-negative
children. In contrast, none of the main severity parameters
differed in the four age groups, irrespective of the presence
of rotavirus.
Conclusions These data provide the evidence that aetiology
and not age determines diarrhoeal severity. The demonstration that diarrhoea was more severe in rotavirus-positive
children supports the need for a rotavirus vaccine and for
studies that address the duration of vaccine protection.
Keywords Rotavirus . Diarrhoea . Children .
Gastroenteritis . Dehydration

G. Izzi
Pediatria ed Oncoematologia, Azienda Ospedaliera Universitaria,
Parma, Italy
R. Virdis
Dipartimento Materno Infantile,
Azienda Ospedaliera Universitaria,
Parma, Italy

A. Cascio
Clinica Malattie Infettive Dipartimento Patologia Umana,
Universit di Palermo,
Palermo, Italy

P. Pecco
Ospedale Regina Margherita,
Turin, Italy

L. Titone
Istituto di Patologia Infettiva e Virologia,
Palermo, Italy

N. Principi
Dipartimento di Pediatria, Universit di Milano,
Milan, Italy

S. Arista
Dipartimento di Igiene e Microbiologia, Universit di Palermo,
Palermo, Italy

M. Fontana
Ospedale UO Pediatria, Ospedale dei Bambini V. Buzzi,
Milan, Italy

242

Abbreviations
EIA enzyme immunoassay
PCR polymerase chain reaction

Introduction
It is generally believed that, irrespective of aetiology,
infants and younger children are at greater risk of severe
gastroenteritis than older children because of their immature
homeostatic fluid mechanisms and immune response [8,
13]. Rotavirus is the most frequent agent cause of
childhood diarrhoea worldwide and rotavirus-induced gastroenteritis is more severe than that caused by other enteric
pathogens. Rotavirus is, therefore, responsible for a
substantial number of hospitalisations [10, 12, 23, 27].
Since rotavirus has a striking age-related distribution,
peaking in infants from 6 to 24 months old [19, 26], it is
not clear whether its increased severity is related to age or
to features intrinsic to the agent.
It has been estimated that a vaccine would prevent as
many as 3.5 million cases annually among children below
5 years of age and 50,000 hospitalisations each year in the
USA [32]. In 1998, an anti-rotavirus vaccine became
commercially available and the Advisory Committee on
Immunization Practices (ACIP) recommended its use [4].
However, it was soon withdrawn because it was implicated
in intestinal intussusception [5, 6, 22]. New vaccines are
under evaluation [25, 31]. However, before implementing a
routine immunisation programme against rotavirus infection, the magnitude of the problem and the expected
benefits of a vaccine must be assessed.
The aim of this multicentre, hospital-based, prospective
survey was to test the hypothesis that the increased severity
of rotavirus-associated gastroenteritis is not due to its age
distribution but to features intrinsic to the virus itself.

Patients and methods

The study was performed in eight hospitals located in six
Italian towns (Naples, Turin, Vicenza, Palermo, Parma and
Milan). The study protocol was agreed upon by paediatricians, microbiologists and a statistician at a specific
investigators meeting. All children aged between 1 month
and 4 years admitted to hospital for at least 48 h because of
acute diarrhoea were prospectively enrolled over 12 months
of observation. Children were excluded if they had received
antibiotics in the previous seven days or if they had
conditions related to immune deficiency. Diarrhoea was
defined as the passage of three or more liquid or semiliquid stools per day. The duration of diarrhoea was the

Eur J Pediatr (2007) 166:241247

time from the first to the last output of abnormal stools

preceding two normal stools. Hospital admission was
decided by the medical staff of each hospital, which did
not include the investigators taking part in the study unless
they were on duty in the emergency room.
Upon admission to hospital, the following information
was collected on a specific form: age, sex, body weight,
duration of diarrhoea prior to admission and the main
reason for admission. Clinical assessment was initially
performed in the emergency room and, subsequently, every
day during hospitalisation. The following parameters were
recorded: body weight, number of stools per day, stool
consistency (defined as solid, loose or liquid and
were scored accordingly), vomiting episodes and body
temperature. Hydration status was assessed daily using the
Gorelick score [14]. Diarrhoea was treated with oral and/or
parenteral rehydration. Specific drugs were not used unless
considered necessary in individual cases by the medical
staff.
The severity of diarrhoea was established using a
validated score devised by Ruuska and Vesikari [26], in
which points are assigned to: length of hospital stay,
maximal frequency and duration of diarrhoeal stools,
maximal frequency and duration of vomiting, maximal
body temperature and severity of dehydration. The maximal
score is 20. Gastroenteritis was considered mild at a score
between 07, moderate between 814 and severe between
1520. The score for each child enrolled in the study was
estimated upon discharge from hospital. To compare the
disease severity in relation to age, the children were divided
into four age groups: 06 months, 712 months, 13
24 months and >24 months.
Stool specimens were collected from all children and
tested for rotavirus with an enzyme immunoassay with antirotavirus antibody (Rotazyme test, Abbott Laboratories,
Rome, Italy).
All positive samples were frozen and shipped for
confirmation to a reference laboratory, where they were
analysed for G type by enzyme immunoassay (EIA) using
type 1-, 2-, 3- and 4-specific neutralising monoclonal
antibodies reactive with viral protein VP7 [9]. The strains
that were not typeable by EIA were analysed by a seminested polymerase chain reactions (PCR) using primers
specific for G1G4 and G9 types [15].
The samples were also examined for Salmonella,
Shigella, Yersinia and Campylobacter, but very few proved
to be positive. We therefore evaluated the severity of
diarrhoea in rotavirus-positive and in rotavirus-negative
children rather than according to specific non-rotavirus
pathogens.
The parents of eligible children were informed of the
study design and were asked to sign a specific consent
form. Children whose parents did not sign the consent form

Eur J Pediatr (2007) 166:241247

243

were included in the epidemiologic analysis but not in the

clinical evaluation analysis.
Statistical analysis
We used the BMDP statistical software (Biomedical
Computer Programs, Berkeley, University of California
Press, Los Angeles, CA, USA) for statistical analyses.
Mean values for continuous variables were compared using
the t-test or the Mann-Whitney test. Differences between
proportions were assessed by the chi-square test or by
Fishers exact test. The adopted level of significance was
<0.05.

Results
A total of 911 children (480 males; mean age
17.913.3 months, range 148 months) with acute diarrhoea were enrolled in the study.
The distribution of children admitted for diarrhoea
showed an evident seasonal pattern, with a winter outbreak
that peaked in March with 16% of all yearly admissions.
The magnitude of the total winter peak of diarrhoeaassociated disease accounted for an average of 40% of all
diarrhoea-associated hospitalisations.
Rotavirus infection was significantly more frequent
during the winter period: overall 71% (265/372) of all
observed cases of rotavirus diarrhoea occurred between
January and April.
Admission of children negative for rotavirus was
prevalent during the fall (46% of all cases of non-rotaviral
diarrhoea), with a significantly increased prevalence compared to rotavirus diarrhoea in the summer and autumn
(81% and 73% of cases, respectively).
Rotavirus was detected in 381 of 911 (42%) children.
Results of bacterial cultures were available for 46.5%
(424/911) of the enrolled children. A total of 29 (6.8%)
Salmonella, 6 (1.4%) Campylobacter and 1 Shigella
infections were detected and the majority of stool cultures
yielded negative results.

As shown in Table 1, there was no difference between

rotavirus-positive and rotavirus-negative children in terms
of sex, body weight or length.
The mean age was also similar. In addition, the duration
of diarrhoea, i.e. the time from the onset of diarrhoea to the
first observation in the emergency room, was similar, as
was the degree of dehydration at the first clinical
evaluation.
The incidence of rotavirus and non-rotavirus gastroenteritis was similar in children from 124 months (Fig. 1).
Rotavirus-negative diarrhoea was more frequent than
rotavirus-positive diarrhoea in children older than
24 months (66% vs. 34%, p<0.001). Disease severity was
evaluated in children for whom complete clinical data were
available. Children with confounding conditions were also
excluded. A total of 123 children were excluded because of
incomplete data and permission to use personal data was
not obtained for 64 children. In addition, 135 children were
excluded because they had other underlying conditions or
concomitant acute infections (generally of the respiratory
tract). Overall, the clinical data of 589 children were
analysed. Their aetiological pattern and age distribution
reflected that of the whole population.
Table 2 shows the individual items that constitute the
diarrhoea severity scores together with the total scores of
children with and without rotavirus.
The mean total duration of diarrhoea was 5.60.1 days
but was significantly longer in rotavirus-positive children
than in rotavirus-negative children. In parallel, hospital
stays were longer in rotavirus-positive children than in
rotavirus-negative children.
Children with rotavirus diarrhoea had a more severe
clinical course than rotavirus-negative children. The degree
of dehydration was greater in rotavirus-positive than in
rotavirus-negative children. There was no difference between the two groups with respect to the degree of
dehydration at the first evaluation in the emergency room
(Table 1). However, the day after admission, 26% of
children with rotaviral gastroenteritis had moderate/severe
dehydration versus 11% of children with non-rotavirus
gastroenteritis (p<0.05). This trend persisted to the second
day of hospitalisation (13% versus 5%; p<0.001). In

Table 1 Characteristics and main clinical features at first evaluation of children admitted to hospitals

Total
Rotavirus+
Rotavirus

Age (months)

Sex (male)

Weight (kg)

Length (cm)

Diarrhoea (days)

Moderate or severe dehydration (n, %)

911
381
(42%)
530
(58%)

18.013.3
17.50.7
(13.8)
18.10.5
(13)

480
200

10.10.2
9.90.2

77.71.0
76.71.1

2.02.1
2.02.0

49 (5.3%)
20 (5.2%)

280

10.40.2

78.50.9

1.92.1

29 (5.5%)

p>0.05 for all variables considered

244

Eur J Pediatr (2007) 166:241247

100

Rotavirus+

90

Rotavirus-

80
70

60

% 50
40
30
20
10
0
0-6

* p<0.01

7-12

13-24

>24

Age groups (months)

Fig. 1 Distribution of children with rotavirus-positive and rotavirusnegative gastroenteritis in age groups. In children older than
24 months, rotavirus-negative diarrhoea was significantly more
frequent than rotavirus-positive diarrhoea (p<0.01)

addition, although the incidence of vomiting was similar,

the number of episodes of vomiting was significantly
higher in rotavirus diarrhoea patients, with vomiting
becoming a more frequent feature the day after admission
(data not shown). As a result, parenteral rehydration was
more frequent, and lasted longer, in children with rotaviral
gastroenteritis (74/222, 33%- vs. 93/367, 25%-; p<0.05
and, respectively, 1.10.1 days versus 0.70.1 days;
p<0.001). Other parameters included in the severity score
(body temperature and maximal frequency of diarrhoeal
stools) showed an increased incidence, intensity and/or
duration in rotavirus gastroenteritis. Overall, as judged by
the score, gastroenteritis was more severe in children with
rotaviral diarrhoea than in children affected by other or not
detected enteric pathogens (Table 2).
Fifty-six children (9.5%) had severe acute gastroenteritis
(i.e. a score 15) and most were rotavirus-positive (36/56).
Thus, severe gastroenteritis was significantly more common

Table 2 Clinical features constituting the scoring system to

evaluate the severity of diarrhoea in children with and
without rotavirus

*The highest score of each

child during 24 h was
included in the analysis

Duration of total diarrhoea (days)

Duration of hospitalisation (days)
Incidence of vomiting
Vomiting (episodes/day)
Dehydration:
Mild
Moderate/severe
Temperature (C):
<37
37.138.4
38.538.9
>39
>6 stools/24 h
Severity score*

in the rotaviral gastroenteritis group (36/222, 15.7%) than

in the non-rotaviral gastroenteritis group (20/367, 5.4%;
p<0.0001). The incidence of protracted (>15 days) diarrhoea was similar in rotavirus-positive and rotavirusnegative children (7/222 vs. 8/367).
To test the hypothesis that the severity of gastroenteritis
was related to aetiology rather than age, we evaluated the
severity score in the four prospectively established age
groups. The main severity parameters, i.e. total duration of
diarrhoea, length of hospital stay, and the need for and
duration of parenteral rehydration, were not associated with
age. The only age-related specific feature was a lower score
in children between 1 and 6 months of age compared with
older children (Fig. 2).
To verify the concept that rotavirus diarrhoea is
intrinsically more severe, we analysed the severity parameters in rotavirus-positive and rotavirus-negative children,
matched for age. The score was consistently higher in
rotavirus-positive than in rotavirus-negative children in all
age groups (Fig. 3).
Rotavirus serotypes
Of the 381 rotavirus-positive samples, serotyping was
carried out for 344 (90%) cases. One-hundred-and-thirteen
(30%) of the 381 samples could not be serotyped by EIA
and were genotyped. Most strains were G1 (168 by EIA
and 33 by PCR) or G4 (91 by EIA and 12 by PCR). The G9
strain accounted for 9% (30 by PCR); G2 and G3 were less
frequent (2 and 5, respectively). Double G1-G4 serotypes
were detected in 1% of cases (Table 3). Thirty-seven strains
were non-typeable by either method. There was no
association between specific rotavirus serotypes and the
severity of diarrhoea (data not shown).

Rotavirus + (n=222, 38%)

Rotavirus (n=367, 62%)

p value

6.00.2
5.10.2
29%
2.93.0

5.40.2
4.50.2
19%
1.42.0

0.031
<0.0001
0.082
0.02

63%
37%

77%
23%

0.001
<0.001

11%
37%
20%
32%
61%
11.72.9

31%
34%
11%
24%
55%
9.72.8

<0.001
0.47
0.003
0.03
0.048
<0.0001

Severity score

Eur J Pediatr (2007) 166:241247

245
Table 3 Rotavirus serotypes detected in the children enrolled

20
18
16
14
12
10
8
6
4
2
0

0-6

7-12

13-24

>24

Age groups (months)

* = p<0.05

Fig. 2 Severity score of diarrhoea according to age group. The total

score was significantly lower in infants under 6 months compared
with older children (p<0.05)

Discussion
Rotavirus is responsible for a substantial, yet underestimated, number of hospitalisations of children with acute
gastroenteritis [17]. The incidence of rotavirus diarrhoea
requiring hospital admission in children presenting at the
emergency department was 40%, which is similar to that
reported in other European countries [11, 18, 20, 21], but
lower than the 70% rate found in Canada [24].
Our prospective study provides comparative data on the
severity of rotavirus-positive and rotavirus-negative gastroenteritis in children in a hospital setting and shows that
aetiology and not age is the major determinant of severity
in childhood gastroenteritis. This finding is important in
view of the availability of new vaccines against rotavirus in
order to evaluate immunisation programmes.
It is commonly considered that gastroenteritis is more
severe in the first two years of age and this age corresponds
to the peak of rotavirus infection. Rotavirus, in turn, is
regarded as a more aggressive enteric pathogen than other
agents of childhood diarrhoea [16]. Velazquez et al. [30]
showed that the incidence of any type of rotavirus infection
20

Rotavirus+

18

Rotavirus-

Severity score

16

n=55

14

n=49

12

10

n=80
n=66

n=82

n=49

*
n=101

n=107

8
6
4
2
0
0-6 months

7-12 months

13-24 months

>24 months

* = p<0.05

Fig. 3 Severity score in rotavirus-positive and rotavirus-negative

children matched for age. In each age group, the score was
significantly increased in rotavirus-positive children compared to
those who were rotavirus-negative

G1
G2
G3
G4
G1G4
G9
typeable
Non-typeable
Total

EIA G1-4

PCR

Total

168
2
4
91
3

33

201 (58%)
2 (0.6%)
5 (1.5%)
103 (30%)
3 (0.9%)
30 (9%)
344 (100%)
37
381

268

1
12
30
76

is generally highest among infants 614 months old and

decreases in children 2123 months old. They also reported
a high incidence of reinfection. However, subsequent
infections are much less severe and symptoms are negligible in most cases symptoms [29]. Thus, severe rotavirusinduced diarrhoea was strongly related to the first infection.
In fact, 85% of the risk of moderate to severe rotavirusassociated diarrhoea occurred in the first 8 months of life,
15% occurred between ages 9 and 17 months and there was
no risk after the age of 18 months [30]. Because of the
peculiar age distribution of rotavirus, we hypothesised that
the increased severity of rotavirus could be the result of a
more vulnerable (because of the young age) preferred
target. On the other hand, given the high frequency of
rotavirus infection, the increased severity of diarrhoea in
infants and younger children could result from a high
exposure to rotavirus. The only age-related specific pattern
of diarrhoea severity in our study was a decreased severity
in infants younger than 6 months old. In contrast, the
severity of diarrhoea was clearly associated with rotavirus
aetiology. Within each age group, the total severity score
was significantly higher in rotavirus-positive than in
rotavirus-negative children. The episodes of vomiting were
more frequent and lasted longer, and the number of liquid
stools was greater in rotavirus-positive children. Given the
more frequent association between dehydration and vomiting than between dehydration and stool number, vomiting
played a major role in inducing dehydration.
Finally, we did not find an association between clinical
severity and specific viral serotypes. An increased severity
has been reported in children infected with G4 type
rotavirus [3], but this was not confirmed in other studies
[2, 33]. Interestingly, 9% of strains were G9, a serotype that
is increasingly observed worldwide [7], with potentially
important consequences for vaccine efficacy [28].
The increased severity of rotavirus infection is certainly
associated with increased costs for hospital and medical
care. In our study, the total duration of symptoms was
higher in rotavirus-positive than in rotavirus-negative
children and was associated with a longer hospitalisation.

246

A trend towards increased duration of rotavirus diarrhoea has been reported also in an outpatient setting and
was associated with increased costs [1]. It was estimated
that the cost of a single episode of diarrhoea requiring an
office visit was US$289, irrespective of aetiology, but was
US$325 for rotavirus-induced diarrhoea. Our data suggest a
similar pattern for hospitalised children who need more
intensive and longer medical care.
In conclusion, it is now clear that the intrinsic features of
rotavirus rather than age are associated with severe
gastroenteritis in children. Our data show that rotavirus is
an exceedingly frequent and aggressive pathogen that has
substantial clinical and economic consequences. Consequently, efforts aimed at producing a vaccine are well
warranted.
Acknowledgement This work was financially supported by a grant
from the Italian Ministry of Health, 4th AIDS Research Project,
Program 50 D.28.

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