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. 2020 Dec 17;59(1):e02287-20.
doi: 10.1128/JCM.02287-20. Print 2020 Dec 17.

A Clinical Epidemiology and Molecular Attribution Evaluation of Adenoviruses in Pediatric Acute Gastroenteritis: a Case-Control Study

Kanti Pabbaraju  1 , Raymond Tellier  2   3 , Xiao-Li Pang  4   5 , Jianling Xie  6 , Bonita E Lee  7   8   9 , Linda Chui  10 , Ran Zhuo  4 , Otto G Vanderkooi  11 , Samina Ali  7   8 , Phillip I Tarr  12 , Anna Funk  13 , Stephen B Freedman  14   15
Affiliations

A Clinical Epidemiology and Molecular Attribution Evaluation of Adenoviruses in Pediatric Acute Gastroenteritis: a Case-Control Study

Kanti Pabbaraju et al. J Clin Microbiol. .

Abstract

The objective of this study was to characterize the etiological role of human adenovirus (HAdV) serotypes in pediatric gastroenteritis. Using a case-control design, we compared the frequencies of HAdV serotypes between children with ≥3 episodes of vomiting or diarrhea within 24 h and <7 days of symptoms (i.e., cases) and those with no infectious symptoms (i.e., controls). Stool samples and/or rectal swabs underwent molecular serotyping with cycle threshold (Ct) values provided by multiplex real-time reverse transcription-PCR testing. Cases without respiratory symptoms were analyzed to calculate the proportion of disease attributed to individual HAdV serotypes (i.e., attributable fraction). Between December 2014 and August 2018, adenoviruses were detected in 18.8% (629/3,347) of cases and 7.2% (97/1,355) of controls, a difference of 11.6% (95% confidence interval [CI], 9.6%, 13.5%). In 96% (95% CI, 92 to 98%) of HAdV F40/41 detections, the symptoms could be attributed to the identified serotype; when serotypes C1, C2, C5, and C6 were detected, they were responsible for symptoms in 52% (95% CI, 12 to 73%). Ct values were lower among cases than among controls (P < 0.001). HAdV F40/41, C2, and C1 accounted for 59.7% (279/467), 17.6% (82/467), and 12.0% (56/467) of all typed cases, respectively. Among cases, Ct values were lower for F40/41 serotypes than for non-F40/41 serotypes (P < 0.001). HAdV F40/41 serotypes account for the majority of HAdV-positive gastroenteritis cases, and when detected, disease is almost always attributed to infection with these pathogens. Non-F40/41 HAdV species have a higher frequency of asymptomatic infection and may not necessarily explain gastroenteritis symptoms. Real-time quantitative PCR may be useful in differentiating asymptomatic shedding from active infection.

Keywords: adenovirus; clinical findings; emergency; gastroenteritis; molecular epidemiology; pediatric.

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Figures

FIG 1
FIG 1
Study participants.
FIG 2
FIG 2
Human adenovirus distributions across age groupings in children with acute gastroenteritis (cases and healthy controls). Numbers of participants in each age group are as follows: 0 to <6 months, 359 cases and 448 controls; 6 to <12 months, 669 cases and 178 controls; 12 to <18 months, 584 cases and 146 controls; 18 to <24 months, 337 cases and 164 controls; 24 to <60 months, 894 cases and 251 controls; ≥60 months, 504 cases and 168 controls. The denominator reflects the entire cohort of controls and cases tested for human adenovirus.
FIG 3
FIG 3
Adenovirus serotype distribution. (A) Distribution of adenovirus serotypes among all included acute gastroenteritis cases (n = 3,347) and controls (n = 1,355). (B) Distribution of adenovirus serotypes among typeable acute gastroenteritis cases (n = 467) and controls (n = 42) who tested positive for adenovirus.
FIG 4
FIG 4
Box plot of stool cycle threshold (Ct) values of adenovirus. (A) Adenovirus-positive acute gastroenteritis cases (n = 516) (median, 22.8 [IQR, 14.6, 32.7]) versus adenovirus-positive controls (n = 97) (median, 32.3 [IQR, 29.5, 34.1]). Significance was tested by a Mann-Whitney U test (two-sided unadjusted P value of <0.001). (B) Adenovirus F40/41-positive acute gastroenteritis cases (n = 229) (median, 13.8 [IQR, 11.5, 17.3]) versus non-F40/41-positive cases (n = 153) (median, 25.8 [IQR, 20.9, 30.9]). Significance was tested by a Mann-Whitney U test (two-sided unadjusted P value of <0.001). (C) Adenovirus-positive acute gastroenteritis cases with monodetections (n = 250) (median, 17.4 [IQR, 13.0, 26.9]) versus adenovirus-positive cases with codetections (n = 266) (median, 30.4 [IQR, 20.3, 33.7]). Significance was tested by a Mann-Whitney U test (two-sided unadjusted P value of <0.001).
FIG 5
FIG 5
Scatterplots showing the relationship of adenovirus stool cycle threshold (Ct) values and modified Vesikari scale scores with a fitted linear regression line. (A) Adenovirus serotype F40/41 (n = 218) (Pearson correlation coefficient, −0.28; P < 0.0001). (B) Adenovirus non-F40/41 serotypes (n = 144) (Pearson correlation coefficient, −0.16; P = 0.06).
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