INTRODUCTION
Acute gastroenteritis (AGE), which affects billions of individuals globally annually, ranks as the fifth leading cause of mortality in children under 5 years old, resulting in approximately 2.5 million deaths each year.1–3 It poses a continuous threat to public health, particularly among vulnerable populations such as young children, older adults, malnourished individuals, and those with compromised immune systems.4–6
A variety of pathogens, including rotavirus, norovirus, Salmonella, and Campylobacter, have been demonstrated to be causative agents of AGE.2 In an etiological study conducted on children with AGE in Korea from 2004 to 2019, Escherichia coli and Salmonella were identified as the most prevalent bacterial pathogens, followed by Campylobacter.7 The incidence of norovirus infections exhibited a gradual increase and accounted for the majority of viral AGE cases.7 In a recent epidemiological study conducted in Japan, viral AGE was found to be associated with multiple virus infections in 33.1% of cases, with norovirus being the predominant pathogen involved.8 Despite the availability of rotavirus vaccination since 2001 in China, it has not been included in the national immunization program. Luo et al.9 reported that rotavirus remained the primary viral pathogen followed by norovirus among outpatient children with AGE in Guangzhou, China. However, comprehensive investigations encompassing a wide range of pathogens including both bacteria and viruses are rarely reported for AGE patients. Furthermore, there is limited understanding regarding clinical symptoms and coinfection patterns of bacteria and viruses due to constraints imposed by detection methodologies.
This investigation aims to explore the epidemiology of bacterial and viral AGE in outpatients, and to compare clinical characteristics of AGE in children under 5 years old with single versus multiple enteric pathogen infections in China.
MATERIALS AND METHODS
Sample collection.
From January 2014 to December 2015, fecal specimens were prospectively collected from outpatient children under age 5 years diagnosed with AGE at our hospital in Guangzhou, China. Patients who did not provide fecal specimens for laboratory analysis were excluded from the study. The diagnostic criteria for AGE are sudden onset of diarrhea (>3 times) or vomiting (>3 times) in the preceding 24 hours with symptoms lasting no longer than 7 days. Informed consent was obtained from the patients or their parents before fecal specimen collection. Demographic and clinical information of outpatient cases with AGE were acquired through paper-based questionnaires. Laboratory findings in stool, including occult blood (OB) test and white blood cell (WBC) count, were received from patients’ clinical database.
The fresh fecal specimens received in our laboratory, each exceeding 100 µL/150 mg, were promptly stored at –70°C for subsequent investigation. Collected fecal specimens were processed using a NucliSENS easyMAG Lysis Buffer (BioMérieux, Marcy-l’Étoile, France), followed by nucleic acid isolation using the QIAamp MinElute Virus Spin kit (Qiagen, Hilden, Germany). The xTAG Gastrointestinal Pathogen Panel assay (xTAG GPP) was conducted according to the manufacturer’s instructions to detect nine bacteria and three viruses, including Salmonella spp., Shigella spp., Campylobacter spp., Yersinia enterocolitica, Vibrio cholerae, Escherichia coli O157 (E. coli O157), enterotoxigenic E. coli (ETEC) LT/ST, Shiga-like toxin-producing E. coli (STEC) stx1/stx2, Clostridium difficile toxins A/B, rotavirus A, adenovirus 40/41, and norovirus GI/GII.
STATISTICAL ANALYSES
The statistical analysis was conducted using SPSS software (version 21.0, IBM SPSS, Armonk, NY). Comparisons between groups were performed using the chi-square test, Fisher exact test, or Mann–Whitney U test. A P-value <0.05 was considered statistically significant.
RESULTS
Subjects and overall detection.
A total of 456 outpatient children under 5 years (61.4% male) participated in this investigation, with a median age of 14 months. The xTAG GPP assay results revealed that 57.0% (260/456) of the stool specimens tested positive for one or more enteric pathogens, resulting in a total of 335 pathogens (204 bacterial strains and 131 viral strains). Salmonella accounted for the largest proportion (16.9%, 77/456), followed by norovirus (15.4%, 70/456), Campylobacter (12.5%, 57/456), rotavirus (12.3%, 56/456), and C. difficile (10.1%, 46/456). Other enteric pathogens detected, in descending order, included ETEC (2.6%, 12/456), E. coli O157 (1.3%, 6/456), adenovirus 40/41 (1.1%, 5/456), Y. enterocolitica (0.7%, 3/456), STEC (0.4%, 2/456), and Shigella (0.2%, 1/456). Vibrio cholerae was not detected (Table 1).
Distribution of detected pathogens in children with acute gastroenteritis
| Pathogens | Total, N | Single Infection, n (%) | Coinfection, n (%) |
|---|---|---|---|
| Bacteria | 204 | 106 | 98 |
| Salmonella | 77 | 42 (54.55) | 35 (45.45) |
| Campylobacter | 57 | 36 (63.16) | 21 (36.84) |
| Clostridium difficile (toxins A/B) | 46 | 21 (45.65) | 25 (54.35) |
| ETEC | 12 | 3 (25.00) | 9 (75.00) |
| E. coli O157 | 6 | 1 (16.67) | 5 (83.33) |
| STEC | 2 | 1 (50.00) | 1 (50.00) |
| Yersinia enterocolitica | 3 | 1 (33.33) | 2 (66.67) |
| Shigella | 1 | 1 (100.00) | 0 (0.00) |
| Virus | 131 | 85 | 46 |
| Rotavirus A | 56 | 38 (67.86) | 18 (32.14) |
| Norovirus | 70 | 45 (64.29) | 25 (35.71) |
| Enteric adenovirus 40/41 | 5 | 2 (40.00) | 3 (60.00) |
ETEC = enterotoxigenic Escherichia coli; E. coli O157 = Escherichia coli O157; STEC = Shiga-like toxin-producing Escherichia coli.
We also observed that 15.1% (69/456) of the fecal specimens exhibited positivity for a minimum of two pathogens. Among these children with AGE, coinfections involving bacteria and viruses were identified in 35 cases, followed by multiple bacterial infections and multiple viral infections in 29 and five cases, respectively.
Seasonal and age distribution of enteric pathogens in children with AGE.
The seasonal distribution of enteric pathogens in children with AGE is presented in Figure 1. Salmonella and ETEC were predominantly detected during the months of June and July. Rotavirus exhibited its peak occurrence in January, whereas norovirus peaked in February. Campylobacter and norovirus were observed throughout the year. No notable seasonal patterns could be discerned for other enteric pathogens.
Monthly distribution of pathogens in children with acute gastroenteritis. (A) Salmonella, Campylobacter, and Clostridium difficile. (B) Rotavirus A, norovirus, and enteric adenovirus40/4. (C) enterotoxigenic Escherichia coli (ETEC), E. coli O157, Shiga-like toxin-producing E. coli (STEC), Yersinia enterocolitica, and Shigella.
Citation: The American Journal of Tropical Medicine and Hygiene 110, 4; 10.4269/ajtmh.23-0725
Figure 2 illustrates the age distribution of enteric pathogens in children with AGE. Salmonella, Campylobacter, and rotavirus were mostly found in older children (37–60 mouths), whereas norovirus had the highest detection rate among those aged 13–36 months.
Age distribution of pathogens in children with acute gastroenteritis.
Citation: The American Journal of Tropical Medicine and Hygiene 110, 4; 10.4269/ajtmh.23-0725
Among the 46 cases of C. difficile infection, 33 (71.7%) occurred in infants younger than 12 months, accounting for 11% of all cases at this age group. Yersinia enterocolitica, STEC, and Shigella were only observed in older children (37–60 mouths), whereas E. coli O157 was more commonly found in younger children (0–12 months). Notably, there was no significant difference in the median age of children with AGE between single-pathogen infections and coinfections, as shown in Table 2.
Comparison of clinical characteristics in the bacterial and viral infection among children with acute gastroenteritis in Guangzhou, China, 2014–2015
| Variables | Single Bacterial Infection (n = 106) | Single Viral Infection (n = 85) | Coinfection (n = 69) | ||
|---|---|---|---|---|---|
| Viral–Bacterial (n = 35) | Multiple Bacterial (n = 29) | Multiple Viral (n = 5) | |||
| Demographics | |||||
| Male, n (%)* | 59 (55.66) | 54 (63.53) | 23 (65.71) | 19 (65.52) | 4 (80.00) |
| Age range (month) | 1–60 | 0.56–60 | 3–60 | 1–53 | 11–35 |
| Median age in months (IQR)* | 12 (8.00–22.50) | 13 (10.00–23.00) | 14 (11.00–25.00) | 11 (7.50–17.50) | 19 (11.50–29.50) |
| Clinical presentations | |||||
| Fever >37.5 °C, n (%)* | 30 (28.30) | 25 (29.41) | 9 (25.71) | 8 (27.59) | 1 (20.00) |
| Vomit, n (%) | 9 (8.49)† | 40 (47.06) | 13 (37.14) | 5 (17.24) | 3 (60.00) |
| Diarrhea, n (%) | 106 (100.00) | 85 (100.00) | 35 (100.00) | 29 (100.00) | 5 (100.00) |
| Frequency (times/day), median (IQR)* | 5 (4.00–6.00) | 5 (4.00–7.00) | 5 (3.00–8.00) | 5.5 (4.00–8.00) | 5 (3.00–5.50) |
| Laboratory findings in stool | |||||
| WBC (/HP), n (%) | 20 (18.87) | 1 (1.18)‡ | 8 (22.86) | 5 (17.24) | 0 (0.00) |
| OB positive, n (%) | 58 (54.72)§ | 13 (15.29) | 9 (25.71) | 9 (31.03) | 0 (0.00) |
| Vesikari score* | 4 (3–5) | 5 (4–7) | 4 (2–7) | 5 (3–6) | 5 (3–8) |
HP = high power field; IQR = interquartile range; OB = stool occult blood test; WBC = white blood cell count.
P >0.05, single bacterial infection compared with single viral infection, viral–bacterial coinfection, and multiple bacterial coinfection; single viral infection compared with viral–bacterial coinfection and multiple viral coinfection.
P <0.05, compared with single viral infection and viral-bacterial coinfection.
P <0.05, compared with single bacterial infection and viral–bacterial coinfection.
P <0.05, compared with single viral infection, viral–bacterial coinfection, and multiple bacterial coinfection.
Clinical features of enteric pathogen infections in children with AGE.
Pairwise comparisons were conducted to assess the clinical features of single bacteria/virus infections and coinfections involving multiple pathogens (Table 2). Similar to single bacterial infections versus single viral infections (P <0.0001), significant differences in vomiting were also observed between single bacterial infections and viral–bacterial coinfections (P <0.0001). Single bacterial infections exhibited a higher likelihood of obtaining a positive result on the OB test compared with single viral infections (P <0.0001), viral–bacterial coinfections (P = 0.0034), and multiple bacterial coinfections (P = 0.0351). Significant differences in WBC count were found between two groups, including single viral infections versus single bacterial infections (P <0.0001) and single viral infections versus viral-bacterial coinfections (P = 0.0002). However, no significant differences in the clinical characteristics such as gender, age, fever, or diarrhea frequency were observed among cases of single bacterial/viral infections and coinfections of viral–bacterial, multiple bacteria and multiple virus. The clinical Vesikari score was used to evaluate the severity of diseases, and the median Vesikari score for these five groups ranged from 4 to 5. There was no statistically significant difference in disease severity between AGE children with single bacterial/viral infections and those exhibiting coinfections.
DISCUSSION
As one of the most prevalent global illnesses, AGE has garnered significant attention from researchers. Although numerous epidemiological studies have primarily focused on viral and bacterial causes of AGE, our understanding regarding the impact of a diverse range of pathogens remains limited.1–3,7,8 Therefore, we conducted a comprehensive investigation in Guangzhou, China, to elucidate the role of viruses and bacteria in this disease.
We could detect pathogens in 57% of AGE children. Consistent with our findings, de Wit et al.10 reported pathogen detection in approximately 40% of the AGE patients. The present study’s detection rate of viral pathogens was 28.7%, which agrees with an early report demonstrating that 20.0% to 30.0% of AGE patients were infected with the virus.11 It is well documented that norovirus and rotavirus are the two major viral pathogens associated with AGE worldwide.12 Rotavirus accounted for 12.3% of all AGE outpatients in our study, consistent with previous studies.13–15 Despite a significant reduction in rotavirus infections due to vaccine introduction and utilization, norovirus has emerged as the predominant cause of viral AGE.16–19 In our study, norovirus was the most common detected viral pathogen, accounting for 15.4% of AGE patients, which aligns with findings from Huzhou (20.2%), the United States (18.5%), Czech Republic (11.8%), and Indonesia (12.3%).20–23 In the sentinel study of Qu et al.,24 diarrheagenic E. coli was detected more frequently, followed by Salmonella and Shigella. Another study of de Wit et al.10 showed that Campylobacter was the most common pathogen, followed by rotavirus, norovirus, and Salmonella. In contrast to the foregoing ranking, our study found that Salmonella (16.9%) was more prevalent than other bacterial pathogens, such as Campylobacter (12.5%), C. difficile (10.1%), and other gut bacteria, which aligns with previous studies in Taiwan and Korea.11,25 Taken together, Salmonella and norovirus were major pathogens in outpatient children under 5 years with AGE, followed by Campylobacter and rotavirus in Guangzhou, China.
In our study, the incidence of rotavirus peaked in January, and norovirus was most commonly detected in February. Our study confirmed the previous findings that most AGE cases occurring during the winter months (December–February) are commonly associated with norovirus or rotavirus.26,27 We also found that Salmonella had a higher detection rate in June and July, which was supported by results from Taiwan.25 Most Salmonella and Campylobacter positive cases were in children aged 37–60 months, which was in line with the report that the proportion of all causative bacteria was highest in children aged 3–5 years.24 Due to the low detection rates, Y. enterocolitica, STEC, Shigella, E. coli O157, and adenovirus showed no variation with age.
Notably, 71.7% of C. difficile–positive detections in this study were observed in children younger than 12 months, and more than half of the outpatients with C. difficile positivity had one or more co-detected pathogens. Hung et al.28 reported that asymptomatic colonization of C. difficile is prevalent among infants. However, accumulating evidence suggests that 4.8% to 19.8% of AGE cases in infants and young children are associated with C. difficile.17,29–31 These findings underscore the need for further investigation into recent antibiotic use, chemotherapy treatment, or hospitalization as potential factors contributing to AGE caused by C. difficile infection. In general, a comprehensive understanding of the etiology and epidemiology of AGE in children warrants continuous monitoring due to regional variations in pathogen prevalence.
Although numerous studies have reported on bacteria- or virus-related AGE in outpatients worldwide, there is a paucity of clinical data comparing the features of multiple pathogen infections to those caused by single pathogens. The current study revealed a coinfection rate of 15.1% among children with AGE, which is consistent with the range of 10% to 17% reported in previous studies.25,32,33 Notably, our findings highlight norovirus and Salmonella as the most frequently detected pathogens responsible for coinfection, corroborated by data from other research groups.25,32,33 Pairwise comparisons were conducted to assess clinical features between single bacterial/viral infections and coinfections by multiple pathogens in this study. Our findings suggest that bacterial infections are primarily associated with blood and white blood cells in the stool, whereas vomiting is frequently observed in cases of viral infections, consistent with previous research.34,35
Researchers in China and elsewhere have reached divergent conclusions regarding whether coinfection contributes to more severe clinical symptoms.34–36 Our data demonstrate that there is no statistically significant difference in disease severity between children with AGE who have single bacterial/viral infections and those with coinfections. However, determining the specific pathogen responsible for the clinical symptoms in cases of multiple pathogen infections remains a challenge. The interactions among multiple pathogens within the human intestinal system are still poorly understood. It is reasonable to speculate that coinfection is relatively common in children with AGE; however, interpreting the detection of multiple targets on a multiplex panel in a clinical context poses uncertainties.37 Therefore, further investigations into pathogen load and underlying mechanisms are warranted.
The limitations of our study include the inclusion of data from only a 2-year period. Overall detection rates could have been enhanced by incorporating astrovirus and sapovirus, which were not targeted pathogens in the xTAG GPP assay. Furthermore, none of the 196 fecal specimens yielded positive pathogen detection; however, alternative enteropathogen multiplex nucleic acid amplification tests capable of detecting various bacteria and viruses may have provided positive results.
In conclusion, our data unequivocally substantiate Salmonella and norovirus as the predominant pathogens accountable for AGE in outpatient children aged younger than 5 years in Guangzhou, China. Furthermore, this comprehensive dataset significantly contributes to enhancing our understanding of the clinical manifestation and disease severity associated with co-infecting pathogens.
ACKNOWLEDGMENTS
We thank the participants for their contributions to the study. In addition, we greatly benefitted from the research studies, mentorship, and friendship of the late Dr. Xiaoyan Che.
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