Abstract
Background
Infections by previously underdiagnosed viruses astrovirus and sapovirus are poorly characterized compared with norovirus, the most common cause of acute gastroenteritis.
Methods
Children <18 years old with acute gastroenteritis were recruited from pediatric emergency departments in Alberta, Canada between 2014 and 2018. We described and compared the clinical course of acute gastroenteritis in children with astrovirus, sapovirus, and norovirus.
Results
Astrovirus was detected in 56 of 2688 (2.1%) children, sapovirus was detected in 146 of 2688 (5.4%) children, and norovirus was detected in 486 of 2688 (18.1%) children. At illness onset, ~60% of astrovirus cases experienced both diarrhea and vomiting. Among sapovirus and norovirus cases, 35% experienced diarrhea at onset and 80% of 91% (sapovirus/norovirus) vomited; however, diarrhea became more prevalent than vomiting at approximately day 4 of illness. Over the full course of illness, diarrhea was 18% (95% confidence interval [CI], 8%– 29%) more prevalent among children with astrovirus than norovirus infections and had longer duration with greater maximal events; there were a median of 4.0 fewer maximal vomiting events (95% CI, 2.0–5.0). Vomiting continued for a median of 24.8 hours longer (95% CI, 9.6–31.7) among children with sapovirus versus norovirus. Differences between these viruses were otherwise minimal.
Conclusions
Sapovirus infections attended in the emergency department are more similar to norovirus than previously reported, whereas astrovirus infections have several distinguishable characteristics.
Keywords: astrovirus, emergency department, gastroenteritis, norovirus, sapovirus
Diarrhea was more prevalent, longer, and more intense in children with astrovirus-associated gastroenteritis than in children with norovirus infections; vomiting also persisted longer but was less intense. Sapovirus and norovirus infections were similar, differing only in sapovirus’ longer vomiting duration.
Molecular diagnostic testing can detect an expanding array of enteropathogens in children with acute gastroenteritis [1], prompting the recognition that 2 previously underdiagnosed viruses, astrovirus and sapovirus, are important contributors to the gastroenteritis burden [2]. However, diagnostic stewardship encourages judicious use of molecular enteropathogen testing panels [3, 4], and leading organizations do not recommend routine stool testing for children with gastroenteritis [5, 6]. Without microbiological confirmation, providers are left with clinical and epidemiological indicators to differentiate astrovirus and sapovirus from one another and from more common viruses, such as norovirus since the implementation of routine rotavirus immunization programs. It is unfortunate that infection by these viruses has been poorly characterized, with most studies including fewer than 50 children, and only 1 study was conducted in North America [7–15]. Larger studies have been community-based and restricted in age, reflecting milder forms of illness rather than those most likely to be seen clinically [16–18]. The clinical features of children of all ages presenting for emergency department (ED) care in North America with astrovirus and sapovirus have not yet been described.
Available data indicate that astrovirus and sapovirus infections are characterized by mild watery diarrhea, sometimes followed by vomiting, fever, and abdominal pain [7–18]. The clinical picture of norovirus, the leading cause of medically attended [19, 20] and self-managed [21] acute gastroenteritis, is marked by the sudden onset of vomiting and brief overall duration [22]. Symptomatology and epidemiologic features (eg, seasonality) [20, 22] consistent with norovirus infection can guide clinical care (eg, diagnostic testing, treatment, anticipatory guidance). In contrast, inadequate etiologic clarity can limit the early recognition of viral infection, impacting downstream clinical decision making, diagnostic testing, and public health outbreak responses.
To clarify the symptomatology of astrovirus and sapovirus infections, we sought to characterize and compare the type, duration, and intensity of symptoms of pediatric astrovirus-, sapovirus-, and norovirus-associated acute gastroenteritis presenting to the ED for medical care.
MATERIALS AND METHODS
Study Design and Population
We conducted a secondary analysis using data from the Alberta Provincial Pediatric EnTeric Infection TEam (APPETITE) study [23]. Eligible children were <18 years old who presented to 2 pediatric EDs in Alberta, Canada (December 2014 to August 2018) with ≥3 episodes of vomiting or ≥3 episodes of diarrhea in a 24-hour period. Children who had symptoms lasting >7 days, required urgent fluid resuscitation, were known to be neutropenic, presented primarily due to a mental health concern, or were enrolled in the study within the preceding 14 days were excluded.
The caregivers of enrolled participants completed questionnaires at the index ED visit and 14 days later [23]. Caregivers provided information related to symptoms, treatments, and outcomes. Data collected at both time points were combined to describe the full course of illness.
The APPETITE study was approved by the Research Ethics Boards of the University of Calgary (REB14-1122) and University of Alberta (Pro00050790). Informed consent was provided by caregivers, and participant assent was obtained when appropriate.
Objectives
The primary objective was to describe the clinical course of astrovirus-, sapovirus-, and norovirus-associated acute gastroenteritis. The secondary objective was to compare symptoms of astrovirus-, sapovirus-, and norovirus-associated acute gastroenteritis.
Clinical Outcomes
The outcomes were presence, duration, and intensity, measured as the maximal number of events in a 24-hour period, of diarrhea and vomiting; presence of fever; and day of illness on which the child presented to the ED. Symptoms were analyzed across the full course of illness.
Specimen Acquisition and Molecular Testing
Specimen collection, transport, storage, and processing have been described [23, 24]. All viral testing was performed at Alberta Precision Laboratories in Edmonton, Alberta. In brief, 2 rectal swabs and a stool sample from each participant were tested with an in-house gastroenteritis virus panel (GVP) using real-time quantitative polymerase chain reaction (PCR) that detects generic adenovirus, astrovirus, norovirus genogroups I (GI) and II (GII), rotavirus, and sapovirus [25]. The GVP incorporates viral nucleic acid extraction by NucliSENS EasyMag (BioMérieux, Marcy-l’Étoile, France), reverse transcription by SuperScriptII Reverse Transcriptase (Life Technologies, Carlsbad, CA), and a TaqMan-based duplex real-time PCR (Life Technologies) for simultaneous viral detection [25]. The threshold cycle cutoff for a positive result was set at 38 [26]. Specimens were also tested with the Luminex xTAG Gastrointestinal Pathogen Panel (GPP), which detects adenovirus 40/41, norovirus GI and GII, and rotavirus, along with 10 enteric bacteria and 3 protozoal pathogens (Luminex Molecular Diagnostics, Ontario, Canada) (Supplemental Methods) [27]. Bacterial cultures were performed using standardized testing procedures (Supplemental Methods) [23, 24].
Participants were classified as having a positive result for an individual enteropathogen if any specimen tested positive using any of the aforementioned testing methods. Clostridioides difficile was only considered positive when detected in children ≥2 years of age because detection more commonly reflects colonization in children <2 years of age [28]. Participants were classified as having a codetected pathogen if ≥2 pathogens were detected in the same patient.
Statistical Analysis
Daily symptom trajectories were plotted from day of illness onset to resolution of diarrhea and vomiting based on reported start and end of individual symptoms. Our primary analysis was restricted to participants with single pathogen detections. Diarrhea, vomiting, and fever prevalence were summarized with proportions and Wald 95% confidence intervals (CIs). Daily and cumulative prevalence of diarrhea and vomiting were graphed for each virus, with median day of ED presentation. The median diarrhea and vomiting duration and intensity and day of ED presentation were calculated with the bias-corrected, accelerated bootstrap (or percentile bootstrap when the distribution of bootstrap realizations was extremely narrow) 95% CI using the rcompanion package in R [29].
The prevalence ratio (PR) of astrovirus or sapovirus versus norovirus and astrovirus versus sapovirus for diarrhea, vomiting, and fever was modeled using a log-binomial model. Coefficients were exponentiated to obtain PRs. Prevalence in this study refers to having experienced the given symptom at any point during the illness. Median diarrhea and vomiting duration and intensity and day of ED presentation were compared between viruses using quantile regression using the quantreg package in R [30]. Models were restricted to the 2 viruses analyzed, allowing the virus coefficient to be interpreted as the effect of one virus relative to the other. In the primary analysis, models were adjusted for age; we also examined effect modification by age of PR estimates. Analysis was performed using R [31]. We performed a secondary analysis adjusting for codetected pathogens to determine their effect on symptomatology.
We conducted a sensitivity analysis to determine whether the earlier presentation and treatment of children with norovirus might have biased the comparison of symptom duration by adjusting for day of presentation and receipt of antiemetics in the ED.
RESULTS
Of 2725 children enrolled, we collected and tested specimens from 2688 (98.6%) (Figure 1). We detected astrovirus, sapovirus, and norovirus in 86 (3.2%), 229 (8.5%), and 669 (24.9%) participants, respectively. Astrovirus, sapovirus, and norovirus were the sole pathogen detected in 56 of 86 (65.1%), 146 of 229 (63.8%), and 486 of 669 (72.7%) of cases, respectively. Demographic characteristics were comparable across viruses, except for seasonality (Table 1; Supplemental Table S1).
Figure 1.
Children by viral detection status. Children without specimens tested either did not provide a specimen or the specimen was inadequate for testing. Codetected pathogens could include one of the other viruses summarized in the figure; adenovirus, rotavirus, bacteria, or parasites. Clostridioides difficile was only considered a codetected pathogen if the child was >2 years old.
Table 1.
Characteristics of Acute Gastroenteritis Episodes, by Virus, Among Children With No Other Pathogens Detected
| Characteristics | Astrovirus | Sapovirus | Norovirus |
|---|---|---|---|
| (n = 56) | (n = 146) | (n = 486) | |
| Age (months), median (IQR) | 25 (14–49) | 20 (11–42) | 20 (11–51) |
| <12 (months), n (%) | 10 (17.9%) | 39 (26.7%) | 138 (28.4%) |
| 12–23 (months), n (%) | 17 (30.4%) | 39 (26.7%) | 131 (27.0%) |
| 24–59 (months), n (%) | 20 (35.7%) | 46 (31.5%) | 120 (24.7%) |
| ≥60 (months), n (%) | 9 (16.1%) | 22 (15.1%) | 97 (20.0%) |
| Female sex, n (%) | 26 (46.4%) | 73 (50.0%) | 234 (48.1%) |
| Identifies as Indigenous, n (%) | 2 (3.6%) | 10 (6.8%) | 29 (6.0%) |
| Chronic medical condition, n (%) | 5 (8.9%) | 19 (13.0%) | 49 (10.1%) |
| Month of ED visit, n (%) | |||
| January–March | 11 (19.6%) | 48 (32.9%) | 164 (33.7%) |
| April–June | 16 (28.6%) | 29 (19.9%) | 134 (27.6%) |
| July–September | 13 (23.2%) | 19 (13.0%) | 55 (11.3%) |
| October–December | 16 (28.6%) | 50 (34.2%) | 133 (27.4%) |
Abbreviations: ED, emergency department; IQR, interquartile range.
Clinical Course of Illness
The most prevalent symptom in children with only astrovirus detected was diarrhea, reported by 92.9% (95% CI, 86.1%–99.6%) (Table 2), although vomiting was also common (83.9%; 95% CI, 74.3%–93.5%). Diarrhea and vomiting prevalence were similar at illness onset (~60%), and few children acquired new symptoms after the third day of illness (Figure 2; Supplemental Table S2). Astrovirus illnesses were most marked by their diarrhea symptoms, with median duration of 115 (95% CI, 93.4–147) hours and maximal 6 (95% CI, 4–6.5) diarrheal episodes in 24 hours. The median day of ED presentation was day 3 (95% CI, 3–4) of illness.
Table 2.
Symptom Presentation Over Full Duration of Illness, by Virus, Among Children With No Other Pathogens Detected
| Symptom/Presentation | Astrovirus | Sapovirus | Norovirus |
|---|---|---|---|
| n = 56 Estimate | n = 146 Estimate | n = 486 Estimate | |
| (95% CI) | (95% CI) | (95% CI) | |
| Diarrhea, n | 52 | 116 | 369 |
| Present, % | 92.9% (86.1%–99.6%) | 79.5% (72.9%–86%) | 75.9% (72.1%–79.7%) |
| Duration a,b (hrs), median | 115 (93.4–147) | 96.8 (74.6–126) | 82.4 (73.6–96.1) |
| Maximal eventsa, median | 6 (4–6.5) | 4 (4–5) | 4 (4–4) |
| Vomiting, n | 47 | 135 | 475 |
| Present, % | 83.9% (74.3%–93.5%) | 92.5% (88.2%–96.7%) | 97.7% (96.4%–99.1%) |
| Duration a,b (hrs), median | 60.6 (46.7–91) | 71.5 (55–88.4) | 52.3 (43.7–56) |
| Maximal eventsa, median | 4 (3–5) | 7 (5–7) | 8 (7–8) |
| Reported fever a, % | 55.4% (42.3%–68.4%) | 34.7% (26.9%–42.5%) | 40.2% (35.8%–44.5%) |
| ED presentation (day of illness), median | 3 (3–4) | 3 (2–3) | 2 (2–2) |
Abbreviations: CI, confidence interval; ED, emergency department.
NOTE: Cases were included in the estimation of course of illness if the virus indicated was the only pathogen detected.
aOne astrovirus case was missing data on vomiting duration and maximal events. Two sapovirus cases were missing data on diarrhea duration and maximal events. Four and 2 norovirus cases were missing data on diarrhea duration and maximal events, respectively. Two sapovirus cases and 3 norovirus cases had no data available on fever for the full duration of their illness.
bDuration was measured from symptom presentation to resolution.
Figure 2.
Prevalence of diarrhea and vomiting symptoms for sole-detected (top panel) astrovirus (n = 56), (middle panel) sapovirus (n = 146), and (bottom panel) norovirus (n = 486) infections over the full course of illness. Vertical line indicates median day of index visit to emergency department. Dark lines indicate daily prevalence, and light lines indicate cumulative prevalence of symptom.
Among children who tested positive for only sapovirus, 92.5% experienced vomiting (95% CI, 88.2%–96.7%) and 79.5% experienced diarrhea (95% CI, 72.9%–86.0%) across the full course of illness (Table 2). However, at onset, only 35% had diarrhea, whereas 80% vomited, with daily prevalence of diarrhea (60%) surpassing vomiting (54%) on day 4 of illness (Figure 2; Supplemental Table S2). The median duration and intensity of vomiting as measured by median maximal number of vomiting events were 96.8 (95% CI, 74.6–126) hours and 7 (95% CI, 5–7) events in a 24-hour period, respectively. Median day of ED presentation was 3 (95% CI, 2–3).
In children who tested positive for only norovirus, vomiting was almost universal (97.7%; 95% CI, 96.4%–99.1%), in contrast to diarrhea prevalence (75.9%; 95% CI, 72.1%–79.7%) (Table 2). This difference was greatest during the first day of illness (35% with diarrhea vs 91% with vomiting); thereafter, vomiting daily prevalence dropped to 78% on day 2 of illness, 59% on day 3, and 45% on day 4. In contrast, diarrhea daily prevalence initially increased, peaking at 60% on day 3 (Figure 2; Supplemental Table S2). Children with norovirus experienced a median of 8 (95% CI, 7–8) maximal vomiting events per 24 hours, and their median ED presentation was day 2 (95% CI, 2–2).
Supplemental Figure S1 shows daily and cumulative prevalence of diarrhea and vomiting when cases with codetected pathogens were included and adjusted for. As observed for sole detections, diarrhea and vomiting were equally prevalent at onset for children with astrovirus.
Symptom Comparison
Diarrhea prevalence was 18% higher (PR = 1.18; 95% CI, 1.08–1.29) in children with astrovirus than with norovirus, but vomiting prevalence was comparable (Table 3). This was similar to the relative difference in diarrhea prevalence between astrovirus and sapovirus (PR = 1.17; 95% CI, 1.05–1.30). Sapovirus and norovirus differed in neither diarrhea nor vomiting prevalence. Fever was more prevalent among astrovirus cases than either norovirus or sapovirus cases (Table 3).
Table 3.
Symptom Comparison Between Viruses, Adjusted for Age
| Symptom/Presentation | Astrovirus vs Norovirus | Sapovirus vs Norovirus | Astrovirus vs Sapovirus |
|---|---|---|---|
| Estimate | Estimate | Estimate | |
| (95% CI) | (95% CI) | (95% CI) | |
| Diarrhea, PRa | 1.18 (1.08–1.29) | 1.02 (0.93–1.12) | 1.17 (1.05–1.30) |
| Vomiting, PRa | 1.00 (0.89–1.12) | 1.00 (0.95–1.05) | DNC |
| Fever, PRa | 1.38 (1.06–1.79) | 1.00 (0.78–1.28) | 1.57 (1.13–2.18) |
| ED presentation (day of illness), difference in mediansb | 1.2 (0.2–2.0) | 0.9 (−0.5 to 2.3) | 0.5 (−0.8 to 1.6) |
| Duration (hrs), Difference in Mediansb,c | |||
| Diarrhea | 24.8 (7.2–55.3) | 8.5 (−11.6 to 33.7) | 21.6 (−14.7 to 51.7) |
| Vomiting | 9.1 (2.8–36.5) | 24.8 (9.6–31.7) | −10.2 (−25.3 to 18.3) |
| Maximal Events, Difference in Mediansb,d | |||
| Diarrhea | 1.9 (0.8–3.0) | 0.0 (−0.8 to 1.0) | 2.0 (0.3–2.8) |
| Vomiting | −4.0 (−5.0 to −2.0) | −0.3 (−3.5 to 0.7) | −3.0 (−4.0 to 0.1) |
Abbreviations: CI, confidence interval; DNC, did not converge; ED, emergency department; PR, prevalence ratio.
aPrevalence ratio estimates are based on a log-binomial model adjusted for age that included all cases of the 2 viruses being compared. Cases with codetected pathogens were excluded.
bDifference estimates are based on a quantile regression model adjusted for age that included all cases of the 2 viruses being compared. Cases with codetected pathogens were excluded.
cDuration was measured from symptom presentation to resolution.
dMaximal events are measured within a 24-hour period.
Where differences in prevalence existed in the overall analysis, the magnitude of the PR increased with increasing age groups; for example, the PR for fever of astrovirus relative to norovirus was 2.59 (95% CI, 1.80–3.71) in children ≥5 years old (Supplemental Table S3). It is notable that all significant PRs from the overall analysis were nullified in the <12-month-old age group.
Children with astrovirus presented to the ED 1.2 (95% CI, 0.2–2.0) days later than those infected by norovirus (Table 3). Astrovirus diarrhea persisted a median 24.8 hours longer than norovirus (95% CI, 7.2–55.3), and intensity was higher (median 1.9 [95% CI, 0.8–3.0] greater), whereas vomiting intensity was lower (median 4.0 [95% CI, −5.0 to −2.0] fewer maximal events in 24-hours). Sapovirus had comparable disease intensity as norovirus but was characterized by median 24.8 hours longer vomiting duration (95% CI, 9.6–31.7). Astrovirus and sapovirus differed only in diarrhea duration, similar to the difference between astrovirus and norovirus (Table 3).
Adjusting for codetected pathogens accentuated differences between sapovirus and norovirus in diarrhea duration (median difference 23.6 hours; 95% CI, 6.0–37.2), and between astrovirus and sapovirus in vomiting intensity (median difference −2.0 events; 95% CI, −2.9 to −2.0) (Supplemental Table S4). No meaningful changes were observed in the other symptom comparisons.
Sensitivity Analysis
By adjusting for day of presentation, we removed all differences in symptom duration between astrovirus or sapovirus and norovirus (Supplemental Table S5). However, adjusting for receipt of antiemetics in the ED negated only the difference in vomiting duration between astrovirus and norovirus; the difference in diarrhea duration between those 2 viruses and the difference in vomiting duration between sapovirus and norovirus persisted.
Discussion
We found that most children infected by astrovirus, sapovirus, and norovirus experienced both diarrhea and vomiting. The dynamics of these symptoms were similar for sapovirus and norovirus, with vomiting initially prevailing and diarrhea subsequently becoming more common. Diarrhea and vomiting were initially equally prevalent in cases with astrovirus, with few children developing new symptoms beyond the third day of illness. When comparing the viruses, we identified multiple differences between astrovirus and norovirus, reflected in greater diarrhea and fever prevalence, longer duration and greater intensity of diarrhea for astrovirus, and greater intensity of vomiting for norovirus. Differences between astrovirus and sapovirus were similar to the comparison between astrovirus and norovirus, although generally attenuated toward the null. In comparison, sapovirus differed from norovirus only by prolonged duration of vomiting.
Variation in the symptom profiles by age should be noted. Infants <12 months old showed no differences in diarrhea, vomiting, or fever prevalence between any of the viruses, whereas almost all older age groups reflected PR estimates observed when all ages were combined. Infants may be outliers with regard to their clinical presentation because of their early phase of physiologic development or partial protective immunity conveyed via transplacental maternal antibodies and breastfeeding [32] muting their symptoms during the first year of life.
Although our results align with the characterization of astrovirus as a predominantly diarrheal disease, we also found vomiting and fever to be relatively more pronounced than previously reported in the literature. We report a median diarrhea duration of 115 hours (4.8 days), consistent with most reports [7, 9, 10, 12], although outliers range from 2 [13, 16] to 9 [11] days of illness. Diarrhea intensity, in our cohort a median maximal 6 events in 24 hours (95% CI, 4–6.5), is also consistent with existing reports of ≥4 to ≥6 [7, 10–13, 16]. However, 84% of children with astrovirus in our study reported vomiting, which is higher than reported in cohorts comparable in age and level of care (ie, 25%–69%) [9, 11–13, 15]. Fever was also more common in our cohort (55%) than in some (ie, 3%–41%) [7, 11, 15], but not all (ie, 60%–72%), [9, 12] comparable studies. Vomiting and fever prevalence and diarrhea duration were even lower in community-based studies of children <2 years old [10, 16], consistent with previous work in our study population, which showed that children treated in the ED experienced more vomiting episodes compared with those treated at home [21]. Among outpatient and hospitalized children, the consistency of diarrhea characteristics but dissimilarity of vomiting between our study and others may be due to selection. Some studies were restricted to patients with diarrhea [7, 9, 13, 15], and of the 2 that were not, 1 used routinely collected specimens [11]. Routine testing can undersample cases with vomiting, because providers may be less likely to test these children due to the often self-limiting nature of the illnesses, frequently viral etiologies not requiring antimicrobial treatment, and inability of obtaining acceptable stool specimens [33]. Of note, the study that did not exclude vomiting-only cases nor use routinely collected specimens reported one of the highest frequencies of vomiting among its astrovirus cases, 69% [12]. Our results may also be different because no prior studies were conducted in Canada or the United States, and enteric virus strains vary by geographic locations [2].
Several community-based studies have characterized sapovirus, where 8%–60% [8, 15, 18, 34] of children experience vomiting of short duration (ie, median 1–2 days) [8, 17, 18]. The more severe presentation of sapovirus is less well characterized. Outpatient and hospital-based studies restricted to children with diarrhea reported markedly dissimilar frequencies of vomiting: 0% [13] and 73% [14], compared to the 93% we observed. This variability may reflect their small sample sizes, both <25, and the exclusion of vomiting-only cases, which is more problematic for sapovirus than astrovirus detection given the higher frequency of vomiting-only presentations.
We chose to interpret all measures of diarrhea, vomiting, and fever as measures of prevalence, because specimens were obtained after the onset of symptoms; therefore, viruses could have been acquired “after” symptom onset. Given the short length of time elapsed between symptom onset and specimen collection, however, it may be reasonable to assume that this did not occur. If this assumption is made, diarrhea and vomiting cumulative prevalence could be interpreted as cumulative incidence, and prevalence ratios could be interpreted as risk ratios; daily prevalence would remain as daily prevalence.
Given the importance of diagnostic stewardship for molecular enteropathogen testing [3, 4] and recommendations against routine stool testing in children with gastroenteritis [5, 6], symptomatology can play an important role in clinical judgement as to the most likely etiology. Children who tested positive for astrovirus initially experienced a high prevalence of vomiting and diarrhea (Figure 2). Sapovirus and norovirus cases showed greater initial prevalence of vomiting relative to diarrhea, a contrast that may facilitate differentiation from astrovirus at ED presentation. Most astrovirus cases did not experience subsequent onset of diarrhea or vomiting symptoms; however, for sapovirus and norovirus cases, new onset of diarrhea continued through the third or fourth day of illness, usually after the ED visit. Thus, if a child presents in the first day or 2 of illness with symptoms consistent with sapovirus and norovirus, diarrhea will likely follow, and clinicians can provide this anticipatory guidance. In contrast, for all 3 viruses, by the third or fourth day of illness, diarrhea will be the more prevalent symptom because of its longer duration; therefore, if a child presents at this point in illness, inquiring about initial symptoms may better inform etiology.
Our study addresses an important gap in the literature, characterizing the illness course of children presenting for ED care in North America with astrovirus and sapovirus infection. As the most common cause of acute gastroenteritis [19, 35–39], norovirus is a natural comparator for understanding the natural history of astrovirus and sapovirus. Explicating the differences in the natural history of these viruses, such as the duration and intensity of symptoms to expect, can enable clinicians to provide more informed anticipatory guidance to patients. For example, if both diarrhea and vomiting are present at the start of illness (Figure 2), particularly if fever and a high number of diarrhea events per 24 hours are observed from onset, then astrovirus would be more likely than norovirus and imply an extended total disease course. Recognizing the overlap in these symptoms with bacterial enteropathogens, most of which are less prevalent than astrovirus in this population [40], could further inform testing and treatment decisions, discouraging empiric antibiotic use.
In addition, although neither astrovirus nor sapovirus is routinely notifiable in Canada or the United States, understanding the clinical course of infected children could improve early recognition of outbreaks. An accurate clinical profile can increase the recognition of similar cases during an outbreak, facilitating development of a potential case pool. This can ultimately minimize testing and improve public health outbreak surveillance [34, 41].
We hypothesized that sapovirus and norovirus would be associated with similar clinical symptoms as members of the Caliciviradae family [8, 34, 42–44]. Although we identified a full day difference in vomiting duration, that difference disappeared when holding day of ED presentation constant, as did the differences in vomiting and diarrhea duration between astrovirus and norovirus. This could suggest that something occurs at the ED visit to shorten the illness course, namely among norovirus cases, who present to the ED on average 1 day earlier. However, our sensitivity analysis indicated that antiemetic administration at the ED visit likely did not alter the duration of vomiting. Instead, accounting for day of ED presentation could in effect be controlling for initial symptom severity, rather than indicating an impact of the ED visit on duration. Additional work is needed to examine the specific constellation of symptoms influencing day of ED presentation.
Although the incidence of rotavirus in Canada has declined since the implementation of vaccination programs [45], it continues to be detected in many settings. Findings from a French ED cohort (n = 624) support the well established picture of rotavirus as the more severe disease. Ninety-five percent of children experienced diarrhea, with an average of 6.4 events/day, 81% vomiting, with a mean 5.1 events/day, and 71% fever [46]. This is most comparable to our findings for the full course of astrovirus illnesses, but more extreme.
Our study has potential limitations. Not all viral detections by molecular assays imply attribution; they might represent asymptomatic or postinfection viral nucleic acid shedding [47]. In addition, the generalizability of our results is limited to children with sufficiently severe symptoms to be brought for ED care. Although children who seek care are arguably the most important cases to study for clinical applications, milder astrovirus and sapovirus acute gastroenteritis still contribute significantly to the overall disease burden, and such children may experience different symptoms [21]. In addition, most symptoms reported at the index ED visit and 14-day follow-up questionnaire were reported by caregivers and are subject to measurement and recall error. However, no mechanism for systematic reporting bias based on specific pathogen evaluated is postulated.
Conclusions
Children who presented to the ED with astrovirus infections experienced diarrhea and vomiting in equal measure at illness onset, whereas those infected with sapovirus or norovirus almost universally experienced vomiting. These initial differences in symptomatology may help clinicians differentiate astrovirus from sapovirus or norovirus at presentation. However, all 3 viral pathogens induced a significant amount of both symptoms over the full course of illness, with diarrhea often developing later in illness for sapovirus and norovirus. Differentiated symptom profiles contribute to outbreak recognition and informing clinical decision making. The symptom profile of astrovirus overlaps with some bacterial enteropathogens, which may impact testing and treatment decisions. Astrovirus infections differ from norovirus infections based on symptom prevalence, duration, and intensity, suggesting that children believed to have gastroenteritis caused by these pathogens should receive distinct anticipatory guidance, whereas sapovirus and norovirus clinical profiles are sufficiently similar that the same guidance could be provided.
Supplementary Data
Supplementary materials are available at The Journal of Infectious Diseases online. Supplementary materials consist of data provided by the author that are published to benefit the reader. The posted materials are not copyedited. The contents of all supplementary data are the sole responsibility of the authors. Questions or messages regarding errors should be addressed to the author.
Notes
Presented in part: Pediatric Academic Societies (PAS) Meeting, Baltimore, MD, April 2019; International Conference on Emerging Infectious Diseases, Atlanta, GA, August 2018.
Financial support. APPETITE was funded by an Alberta Innovates Team Collaborative Research Innovation Opportunity grant. S. B. F. was funded by the Alberta Children’s Hospital Foundation Professorship in Child Health and Wellness. G. A. M. T. was funded by a Banting Postdoctoral Fellowship, Alberta Innovates Postgraduate Fellowship, and University of Calgary Eyes High Postdoctoral Fellowship.
Potential conflicts of interest. S. B. F. reports the following: grants from Alberta Children’s Hospital Foundation, grants from Alberta Innovates, grants from Alberta Children’s Hospital Research Institute, grants from University of Calgary, during the conduct of the study; and personal fees from Takeda Pharmaceutical Company, outside the submitted work. P. I. T. reports personal fees from Takeda Pharmaceuticals and personal fees and other from MediBeacon Inc., outside the submitted work. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.
Contributor Information
Gillian A M Tarr, Division of Environmental Health Sciences, School of Public Health, University of Minnesota, Minneapolis, Minnesota, USA.
Emily Downey, Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada.
Xiao-Li Pang, Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, Alberta, Canada; Alberta Precision Laboratories-ProvLab, Edmonton, Alberta, Canada.
Ran Zhuo, Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, Alberta, Canada.
Ali J Strickland, Division of Environmental Health Sciences, School of Public Health, University of Minnesota, Minneapolis, Minnesota, USA.
Samina Ali, Department of Pediatrics, Faculty of Medicine & Dentistry, University of Alberta, Edmonton, Alberta, Canada; Women and Children’s Health Research Institute, University of Alberta, Edmonton, Alberta, Canada.
Bonita E Lee, Department of Pediatrics, Faculty of Medicine & Dentistry, University of Alberta, Edmonton, Alberta, Canada.
Linda Chui, Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, Alberta, Canada; Alberta Precision Laboratories-ProvLab, Edmonton, Alberta, Canada.
Phillip I Tarr, Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Washington University in St. Louis School of Medicine, St. Louis, Missouri, USA.
Stephen B Freedman, Departments of Pediatrics and Emergency Medicine, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada; Sections of Pediatric Emergency Medicine and Gastroenterology, Alberta Children’s Hospital, Calgary, Alberta, Canada; Alberta Children’s Hospital Research Institute, Alberta Children’s Hospital, Calgary, Alberta, Canada.
References
- 1. Binnicker MJ. Multiplex molecular panels for diagnosis of gastrointestinal infection: performance, result interpretation, and cost-effectiveness. J Clin Microbiol 2015; 53:3723–8. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2. Becker-Dreps S, González F, Bucardo F. Sapovirus: an emerging cause of childhood diarrhea. Curr Opin Infect Dis 2020; 33:388–97. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3. Messacar K, Parker SK, Todd JK, Dominguez SR. Implementation of rapid molecular infectious disease diagnostics: the role of diagnostic and antimicrobial stewardship. J Clin Microbiol 2017; 55:715–23. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4. Tarr GAM, Tarr PI. Pediatric enteric diagnostic stewardship: the right test in the right context. Pediatrics 2021; 147:e2020044941. [DOI] [PubMed] [Google Scholar]
- 5. Shane AL, Mody RK, Crump JA, et al. 2017 Infectious Diseases Society of America clinical practice guidelines for the diagnosis and management of infectious diarrhea. Clin Infect Dis 2017; 65:e45–80. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6. Guarino A, Ashkenazi S, Gendrel D, Lo Vecchio A, Shamir R, Szajewska H; European Society for Pediatric Gastroenterology, Hepatology, and Nutrition; European Society for Pediatric Infectious Diseases. European Society for Pediatric Gastroenterology, Hepatology, and Nutrition/European Society for Pediatric Infectious Diseases evidence-based guidelines for the management of acute gastroenteritis in children in Europe: update 2014. J Pediatr Gastroenterol Nutr 2014; 59:132–52. [DOI] [PubMed] [Google Scholar]
- 7. Akdag AI, Gupta S, Khan N, Upadhayay A, Ray P. Epidemiology and clinical features of rotavirus, adenovirus, and astrovirus infections and coinfections in children with acute gastroenteritis prior to rotavirus vaccine introduction in Meerut, North India. J Med Virol 2020; 92:1102–9. [DOI] [PubMed] [Google Scholar]
- 8. Rockx B, De Wit M, Vennema H, et al. Natural history of human calicivirus infection: a prospective cohort study. Clin Infect Dis 2002; 35:246–53. [DOI] [PubMed] [Google Scholar]
- 9. Tseng WC, Wu FT, Hsiung CA, et al. Astrovirus gastroenteritis in hospitalized children of less than 5 years of age in Taiwan, 2009. J Microbiol Immunol Infect 2012; 45:311–7. [DOI] [PubMed] [Google Scholar]
- 10. Guerrero ML, Noel JS, Mitchell DK, et al. A prospective study of astrovirus diarrhea of infancy in Mexico City. Pediatr Infect Dis J 1998; 17:723–7. [DOI] [PubMed] [Google Scholar]
- 11. López L, Castillo FJ, Fernández MA, et al. Astrovirus infection among children with gastroenteritis in the city of Zaragoza, Spain. Eur J Clin Microbiol Infect Dis 2000; 19:545–7. [DOI] [PubMed] [Google Scholar]
- 12. Jakab F, Peterfai J, Meleg E, Banyai K, Mitchell DK, Szucs G. Comparison of clinical characteristics between astrovirus and rotavirus infections diagnosed in 1997 to 2002 in Hungary. Acta Paediatr 2005; 94:667–71. [DOI] [PubMed] [Google Scholar]
- 13. Chen Y, Li Z, Han D, et al. Viral agents associated with acute diarrhea among outpatient children in southeastern China. Pediatr Infect Dis J 2013; 32:e285–90. [DOI] [PubMed] [Google Scholar]
- 14. Lasure N, Gopalkrishna V. Epidemiological profile and genetic diversity of sapoviruses (SaVs) identified in children suffering from acute gastroenteritis in Pune, Maharashtra, Western India, 2007-2011. Epidemiol Infect 2017; 145:106–14. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15. Shioda K, Cosmas L, Audi A, et al. Population-based incidence rates of diarrheal disease associated with Norovirus, Sapovirus, and Astrovirus in Kenya. PLoS One 2016; 11:e0145943. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16. Pang XL, Vesikari T. Human astrovirus-associated gastroenteritis in children under 2 years of age followed prospectively during a rotavirus vaccine trial. Acta Paediatr 1999; 88:532–6. [DOI] [PubMed] [Google Scholar]
- 17. Pang XL, Zeng SQ, Honma S, Nakata S, Vesikari T. Effect of rotavirus vaccine on Sapporo virus gastroenteritis in Finnish infants. Pediatr Infect Dis J 2001; 20:295–300. [DOI] [PubMed] [Google Scholar]
- 18. Vielot NA, González F, Reyes Y, et al. Risk factors and clinical profile of sapovirus-associated acute gastroenteritis in early childhood: a Nicaraguan birth cohort study. Pediatr Infect Dis J 2021; 40:220–6. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19. Payne DC, Vinjé J, Szilagyi PG, et al. Norovirus and medically attended gastroenteritis in U.S. children. N Engl J Med 2013; 368:1121–30. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20. Hall AJ, Wikswo ME, Manikonda K, Roberts VA, Yoder JS, Gould LH. Acute gastroenteritis surveillance through the National Outbreak Reporting System, United States. Emerg Infect Dis 2013; 19:1305–9. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21. Vanderkooi OG, Xie J, Lee BE, et al. ; Alberta Provincial Pediatric EnTeric Infection TEam (APPETITE) and Pediatric Emergency Research Canada (PERC). A prospective comparative study of children with gastroenteritis: emergency department compared with symptomatic care at home. Eur J Clin Microbiol Infect Dis 2019; 38:2371–9. [DOI] [PubMed] [Google Scholar]
- 22. Glass RI, Parashar UD, Estes MK. Norovirus gastroenteritis. N Engl J Med 2009; 361:1776–85. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23. Freedman SB, Lee BE, Louie M, et al. Alberta provincial pediatric EnTeric Infection TEam (APPETITE): epidemiology, emerging organisms, and economics. BMC Pediatr 2015; 15:89. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24. Freedman SB, Xie J, Nettel-Aguirre A, et al. ; Alberta Provincial Pediatric EnTeric Infection TEam (APPETITE). Enteropathogen detection in children with diarrhoea, or vomiting, or both, comparing rectal flocked swabs with stool specimens: an outpatient cohort study. Lancet Gastroenterol Hepatol 2017; 2:662–9. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 25. Pang XL, Preiksaitis JK, Lee BE. Enhanced enteric virus detection in sporadic gastroenteritis using a multi-target real-time PCR panel: a one-year study. J Med Virol 2014; 86:1594–601. [DOI] [PubMed] [Google Scholar]
- 26. Zhuo R, Parsons BD, Lee BE, et al. Identification of enteric viruses in oral swabs from children with acute gastroenteritis. J Mol Diagn 2018; 20:56–62. [DOI] [PubMed] [Google Scholar]
- 27. Wessels E, Rusman LG, van Bussel MJ, Claas EC. Added value of multiplex Luminex Gastrointestinal Pathogen Panel (xTAG® GPP) testing in the diagnosis of infectious gastroenteritis. Clin Microbiol Infect 2014; 20:O182–7. [DOI] [PubMed] [Google Scholar]
- 28. Kociolek LK, Patel SJ, Zheng X, Todd KM, Shulman ST, Gerding DN. Clinical and microbiologic assessment of cases of pediatric community-associated Clostridium difficile infection reveals opportunities for improved testing decisions. Pediatr Infect Dis J 2016; 35:157–61. [DOI] [PubMed] [Google Scholar]
- 29. Mangiafico S. rcompanion: functions to support extension education program evaluation. R package version 2.3.21 [software]; 2020. [Google Scholar]
- 30. Koenker R. quantreg: quantile regression. R package version 5.85 [software]; 2021. [Google Scholar]
- 31. R Core Team. R: A Language and Environment for Statistical Computing [computer program]. Vienna, Austria: R Foundation for Statistical Computing, 2017. [Google Scholar]
- 32. Labayo HKM, Pajuelo MJ, Tohma K, et al. Norovirus-specific immunoglobulin A in breast milk for protection against norovirus-associated diarrhea among infants. EClinicalMedicine 2020; 27:100561. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 33. Freedman SB, Xie J, Lee BE, et al. Microbial etiologies and clinical characteristics of children seeking emergency department care due to vomiting in the absence of diarrhea. Clin Infect Dis 2021:ciab451. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 34. Sala MR, Broner S, Moreno A, et al. ; Working Group for the Study of Outbreaks of Acute Gastroenteritis in Catalonia. Cases of acute gastroenteritis due to calicivirus in outbreaks: clinical differences by age and aetiological agent. Clin Microbiol Infect 2014; 20:793–8. [DOI] [PubMed] [Google Scholar]
- 35. Ahmed SM, Hall AJ, Robinson AE, et al. Global prevalence of norovirus in cases of gastroenteritis: a systematic review and meta-analysis. Lancet Infect Dis 2014; 14:725–30. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 36. Hall AJ, Lopman BA, Payne DC, et al. Norovirus disease in the United States. Emerg Infect Dis 2013; 19:1198–205. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 37. Koo HL, Neill FH, Estes MK, et al. Noroviruses: the most common pediatric viral enteric pathogen at a large university hospital after introduction of rotavirus vaccination. J Pediatric Infect Dis Soc 2013; 2:57–60. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 38. Hemming M, Räsänen S, Huhti L, Paloniemi M, Salminen M, Vesikari T. Major reduction of rotavirus, but not norovirus, gastroenteritis in children seen in hospital after the introduction of RotaTeq vaccine into the National Immunization Programme in Finland. Eur J Pediatr 2013; 172:739–46. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 39. Bucardo F, Reyes Y, Svensson L, Nordgren J. Predominance of norovirus and sapovirus in Nicaragua after implementation of universal rotavirus vaccination. PLoS One 2014; 9:e98201. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 40. Tarr GAM, Chui L, Lee BE, et al. Performance of stool-testing recommendations for acute gastroenteritis when used to identify children with 9 potential bacterial enteropathogens. Clin Infect Dis 2019; 69:1173–82. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 41. Hedberg CW, Palazzi-Churas KL, Radke VJ, Selman CA, Tauxe RV. The use of clinical profiles in the investigation of foodborne outbreaks in restaurants: United States, 1982-1997. Epidemiol Infect 2008; 136:65–72. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 42. Desselberger U. Caliciviridae other than noroviruses. Viruses 2019; 11:286. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 43. Lee LE, Cebelinski EA, Fuller C, et al. Sapovirus outbreaks in long-term care facilities, Oregon and Minnesota, USA, 2002-2009. Emerg Infect Dis 2012; 18:873–6. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 44. Oka T, Wang Q, Katayama K, Saif LJ. Comprehensive review of human sapoviruses. Clin Microbiol Rev 2015; 28:32–53. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 45. Muchaal PK, Hurst M, Desai S. The impact of publicly funded rotavirus immunization programs on Canadian children. Can Commun Dis Rep 2021; 47:97–104. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 46. de Rougemont A, Kaplon J, Fremy C, et al. Clinical severity and molecular characteristics of circulating and emerging rotaviruses in young children attending hospital emergency departments in France. Clin Microbiol Infect 2016; 22:737.e9–15. [DOI] [PubMed] [Google Scholar]
- 47. Wu QS, Xuan ZL, Liu JY, et al. Norovirus shedding among symptomatic and asymptomatic employees in outbreak settings in Shanghai, China. BMC Infect Dis 2019; 19:592. [DOI] [PMC free article] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.