Original Article
Astroviruses as a Cause of Gastroenteritis in Children
N Engl J Med 1991; 324:1757-1760June 20, 1991
- Abstract
Background.
Infection with astroviruses has been associated with gastroenteritis in children, and serologic surveys indicate that this infection may be frequent. The importance of astroviruses as agents of gastroenteritis has not been shown in a controlled study, however.
Methods.
We used monoclonal antibody-based enzyme immunoassays to detect astroviruses, enteric adenoviruses, and rotaviruses in stool samples obtained from age-matched children with and children without gastroenteritis. The samples were obtained in two studies, three years apart, among patients attending an outpatient clinic in Bangkok, Thailand.
Results.
In the first study, astroviruses were detected in 8.6 percent (96 of 1111 ) of the children with gastroenteritis and in 2.0 percent (19 of 947) of the children without gastroenteritis. In the second study the rates were 8.6 percent (50 of 580) and 2.1 percent (11 of 512), respectively. For both studies combined, enteric adenoviruses were detected in 2.6 percent of those with gastroenteritis and in 0.5 percent of the controls, whereas rotaviruses were detected in 19 percent of those with gastroenteritis and in 1.0 percent of the controls. The clinical findings associated with astrovirus infection were similar to those associated with rotavirus infection, except for a trend toward greater dehydration in the children infected with rotaviruses.
Conclusions.
These two controlled studies involving a total of 3150 Thai children provide evidence that astroviruses are a common cause of viral gastroenteritis. Astroviruses were found in association with gastroenteritis more frequently than were enteric adenoviruses, and with nearly half the frequency of rotaviruses. (N Engl J Med 1991; 324:1757–60.)
Media in This Article
Table 1
Frequency of Astrovirus Infection in Two Studies in Age-Matched Children with and Children without Gastroenteritis.Table 2
Frequency of Astroviruses, Group A Rotaviruses, Enteric Adenoviruses, and Nonenteric Adenoviruses as Etiologic Agents of Gastroenteritis in Children.Article Activity
- Article
DURING the past 20 years, there have been major advances in our understanding of the cause of viral gastroenteritis. Rotaviruses in particular, as well as enteric adenoviruses, commonly cause diarrhea in infants and young children, and the Norwalk group of viruses frequently produces outbreaks of gastroenteritis in older children and adults. Despite these advances, however, no etiologic agent is identified in nearly half the patients with acute diarrhea, even when all available diagnostic measures are undertaken.1 New infectious causes of gastroenteritis probably remain to be discovered. Furthermore, some viruses, such as astroviruses, are associated with gastroenteritis, but their medical importance remains poorly defined.
Astroviruses were first associated with gastroenteritis in 1975 in a report by Madeley and Cosgrove,2 who with electron microscopy visualized viruses that were 28 nm in diameter and had star-shaped surfaces in stools from infants with gastroenteritis. Subsequent electron-microscopical studies have also found astroviruses in the stools of patients with gastroenteritis.3 4 5 6 7 8 However, astrovirus infection has not been firmly established as a cause of gastroenteritis in humans, because of the lack of controlled studies and the small numbers of patients studied.9 10 11 Infection in newborns is generally asymptomatic, although some have mild symptoms.6 , 7 Astroviruses have occasionally been associated with outbreaks of diarrhea in adults,12 , 13 but in a study among adult volunteers, symptoms developed in only 1 of 17 persons, although seroconversion occurred in 13 of the 16 who were tested.14 Serologic surveys for antibody prevalence have not been extensive, but in one study of 87 children in England, 64 percent became seropositive by the age of 4 years and 87 percent by the age of 10 years.15 This finding suggests that astrovirus infections may be common, but the actual incidence of astroviruses as etiologic agents of gastroenteritis is not established, primarily because there are no convenient techniques of identification and detection.
Cultivation of astroviruses was first reported in 1981 by Lee and Kurtz,16 who later determined that there are five serotypes, as distinguished by immunofluorescence.17 We later confirmed the cultivation of astroviruses,18 and also cultivated a putative Norwalklike virus, the Marin County agent, and showed that it was actually an astrovirus.19 , 20 The isolation of virus from clinical samples in cell culture is inefficient, however, and requires several serial passages.
As previously reported,18 19 20 21 we have demonstrated the presence of an astrovirus group antigen shared by all human serotypes, prepared monoclonal antibodies to that antigen, and developed a sensitive enzyme immunoassay for detecting astrovirus antigen in stools. We report here the use of the assay to determine the frequency of astrovirus infection in children with gastroenteritis and in age-matched patients without gastroenteritis. This allowed us to assess the role of astroviruses in gastroenteritis, as well as to determine the medical importance of astrovirus infection as compared with that of the established viral pathogens of pediatric diarrhea, rotaviruses and enteric adenoviruses.
Methods
Patients
During two one-year periods, stool specimens were obtained from 3150 children under the age of five at an outpatient clinic in Bangkok, Thailand. In the first study, in 1985—1986, stools were obtained from 1111 children with gastroenteritis and also from 947 children of similar ages who visited the clinic for other reasons. Eighty-four percent of these specimens were from children less than two years old, and 55 percent were from children less than one year old. In the second study, in 1989, stools were obtained from 580 patients less than six months old who had gastroenteritis and from 512 age-matched children who did not. Most patients with gastroenteritis could be matched for age with controls, but for some, control samples were not available. Details of the epidemiologic characteristics and the design of these studies are described elsewhere.22 Stools from all children were tested for cryptosporidium and intestinal parasites and for bacterial pathogens, including salmonella species, shigella species, enteroinvasive, enteropathogenic, enterohemorrhagic, and enterotoxigenic Escherichia coli, Campylobacter jejuni, Plesiomonas shigelloides, and vibrio species, by previously described methods.23 The stools were frozen and stored at — 70°C for later viral testing.
Virologic Testing
All stool samples were tested as 10 percent (wt/vol) suspensions in 0.01 M phosphate-buffered saline (pH 7.0) for astroviruses, adenovirus group antigen, enteric adenoviruses (Ad40 and Ad41), and group A rotaviruses by monoclonal antibody—based enzyme immunoassays. We had previously determined with clinical specimens that all the assays were comparable to electron microscopy in terms of sensitivity and specificity.21 , 24 , 25 For the detection of astroviruses we used an indirect double-antibody assay, with monoclonal antibody as the capture antibody and rabbit antiserum as the detector antibody.21 The antiserum was prepared against astrovirus type 2 but is group reactive on enzyme immunoassay.21 The enzyme immunoassays for the types of enteric adenovirus were performed with a mixture of monoclonal antibodies to each type.24 For the detection of adenovirus group antigen, a monoclonal antibody to adenovirus hexon group antigen,26 obtained from the American Type Culture Collection (Rockville, Md.), was substituted for the Ad40 and Ad41 mixture of monoclonal antibodies in the assay.24 The assay for the detection of group A rotavirus25 used a monoclonal antibody to rotavirus VP6 antigen.27 The substrate for peroxidase was 0-phenylenediamine and hydrogen peroxide (Abbott Laboratories, North Chicago), and the reactions were stopped with 1 N of sulfuric acid. The absorbance of the solutions was measured at 490 nm in a plate-reader spectrophotometer. Samples were considered positive for viruses if the absorbance value was more than 0.1 and more than three times that of the negative control (stool diluent or negative stool sample in phosphate-buffered saline).
Statistical Analysis
For comparisons of disease status with viral-excretion status, summarized in two-by-two tables, Fisher's exact test was used to evaluate the level of significance. The chi-square test and Student's t-test were used to validate various comparisons. All tests were two-tailed. We also tested for sets of viruses, bacteria, and parasites that distinguished between patients with gastroenteritis and those without by means of a multivariate method, stepwise logistic regression. The bacteria and parasites were those listed above.
Results
Astrovirus Infections
In both studies, astrovirus infection was highly associated with gastroenteritis. In the first study, 8.6 percent of the children with gastroenteritis were infected with astroviruses, as compared with 2.0 percent of the controls; in the second study, the figures were 8.6 and 2.1 percent (P<0.001) (Table 1Table 1
Frequency of Astrovirus Infection in Two Studies in Age-Matched Children with and Children without Gastroenteritis.). In the first study, 45 percent of the patients with gastroenteritis who were infected with astroviruses were ≤6 months old, 78 percent were ≤1 year old, and 95 percent were ≤2 years old. Of those with gastroenteritis who were infected with rotaviruses, 25 percent were ≤6 months old, 57 percent were ≤1 year old, and 90 percent were ≤2 years old. All the patients in the second study were ≤6 months old.The relative importance of astroviruses as compared with the other viruses we detected in the samples is shown in Table 2Table 2
Frequency of Astroviruses, Group A Rotaviruses, Enteric Adenoviruses, and Nonenteric Adenoviruses as Etiologic Agents of Gastroenteritis in Children.. Astroviruses were identified in stools more often than enteric adenoviruses, and astroviruses accounted for almost half as many illnesses as rotaviruses. In the first study, enteric adenoviruses were detected in 3 percent (34 of 1111) of the children with gastroenteritis and 0.8 percent (8 of 947) of those who did not have the condition; in the second study the respective values were 1.7 percent (10 of 580) and 0 percent (0 of 512). The rates of rotavirus excretion in children with and children without gastroenteritis were 19.8 percent (220 of 1111) and 0.7 percent (7 of 947), respectively, in the first study, and 17.6 percent (102 of 580) and 1.6 percent (8 of 512) in the second. Infections with rotaviruses and astroviruses occurred throughout the year, peaking in the fall and winter.Infections with some enteric bacterial pathogens are common in this population in both children with and children without diarrheal symptoms.22 Because of the frequency of bacterial infection, there are often coinfections with bacterial and viral pathogens as well. In the present investigation, we also found frequent coinfections of astroviruses and rotaviruses. In the first study, 36 of the 96 patients with astrovirus infections also had rotavirus infections, and in the second study rotaviruses were found in 12 of the 50 samples positive for astroviruses. To validate that astrovirus infection alone distinguished patients with gastroenteritis from those who did not have the condition, we examined the data on all the viral, bacterial, and parasitic agents simultaneously by means of stepwise logistic regression. We determined by this method that astrovirus infection was independently associated with gastroenteritis in both studies (P<0.0001).
Clinical Correlation
To assess further the role and medical importance of astroviruses in gastroenteritis, we compared the clinical symptoms of the children with gastroenteritis who were infected with only astroviruses with the symptoms of those who were infected with only rotaviruses; children with other bacterial, viral, or parasitic infections were excluded. The results are shown in Table 3Table 3
Clinical Findings Associated with Astrovirus and Rotavirus Gastroenteritis.*. The frequency of the clinical findings with each of the two infections was similar, and there were no significant differences in any of the categories evaluated. Dehydration (≥5 percent) was somewhat more common with rotavirus infection (P<0.08).The rate of hospitalization was low in children with rotavirus or astrovirus infection, but a slightly higher percentage of the hospitalized children had rotavirus infection alone than had astrovirus infection alone (3.4 percent [6 of 175] vs. 2.3 percent [1 of 44]). This difference may have been due to the higher rate of dehydration (≥5 percent) among the children with rotavirus infection (27 of 175 vs. 2 of 44).
Discussion
From these two controlled studies in Thailand, we conclude that astroviruses are etiologic agents of gastroenteritis. This conclusion is based on data from a large number of stool samples (3150) from children with and children without gastroenteritis, including a sufficient number who had astrovirus infection in the absence of other pathogens. This allowed us to correlate astrovirus excretion with specific clinical findings. The clinical syndrome produced by astroviruses was indistinguishable from that produced by rotaviruses, except that a higher percentage of children with rotavirus infection had dehydration ≥5 percent.
Coinfections with astroviruses and rotaviruses were noted in each of our studies. Coinfections have also been found in previous studies that examined diarrheal stools for viruses by electron microscopy.3 , 28 In one of those studies,28 11 of 28 stools positive for astroviruses were also found to be positive for rotaviruses. We did not find that combined infection resulted in more severe symptoms (data not shown).
The incidence of astrovirus infection in children with gastroenteritis was 8.6 percent in both studies, although the samples in the second study were collected approximately three years after those in the first study. No significant differences in clinical findings were noted between the two studies (data not shown). The incidence of astrovirus infection in this population and the clinical findings that result therefore appear to be consistent over at least a three-year period.
We conclude that astroviruses are medically important agents of gastroenteritis that produce clinical findings similar to those caused by rotavirus infection. Astroviruses were associated with illness more frequently than were enteric adenoviruses, and they were associated with almost half (45 percent) as many illnesses as rotavirus infection.
Supported by grants from the Thrasher Research Fund and the World Health Organization, and by a contract (DAMD 17–86–C6196) from the U.S. Army Medical Research and Development Command.
We are indebted to Dr. Robert A. Lew for the statistical analyses and to Nancy A. Nowak, Richard W. Hudson, Dorothy Perron-Henry, and Emily Clements for their excellent technical assistance.
Source Information
From the Division of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester (J.E.H., N.R.B.), and the Armed Forces Research Institute of Medical Sciences, Bangkok, Thailand (D.N.T., P.E.). Address reprint requests to Dr. Herrmann at the Division of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, MA 01655.
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