Assessment of blood enterovirus PCR testing in paediatric populations with fever without source, sepsis-like disease, or suspected meningitis: a prospective, multicentre, observational cohort study

Abstract

Background Enteroviruses are the most frequent cause of acute meningitis and are seen increasingly in sepsis-like disease and fever without source in the paediatric population. Detection of enterovirus in cerebrospinal fluid (CSF) specimens by PCR is the gold standard diagnostic test. Our aim was to assess a method of detecting enterovirus in blood specimens by PCR. MethodsWe did a prospective, multicentre, observational study at 35 French paediatric and emergency departments in 16 hospitals. We recruited newborn babies (aged ≤28 days) and infants (aged >28 days to ≤2 years) with fever without source, sepsis-like disease, or suspected meningitis, and children (aged >2 years to ≤16 years) with suspected meningitis, who were admitted to a participating hospital. We used a standardised form to obtain demographic, clinical, and laboratory data, which were anonymised. Enterovirus PCR testing was done in blood and CSF specimens. Findings Between June 1, 2015, and Oct 31, 2015, and between June 1, 2016, and Oct 31, 2016, we enrolled 822 patients, of whom 672 had enterovirus PCR testing done in blood and CSF specimens. Enterovirus was detected in 317 (47%) patients in either blood or CSF, or both (71 newborn babies, 83 infants, and 163 children). Detection of enterovirus was more frequent in blood samples than in CSF specimens of newborn babies (70 [99%] of 71 vs 62 [87%] of 71; p=0·011) and infants (76 [92%] of 83 vs 62 [75%] of 83; p=0·008), and was less frequent in blood samples than in CSF specimens of children (90 [55%] of 163 vs 148 [91%] of 163; p<0·0001). Detection of enterovirus was more frequent in blood samples than in CSF specimens of infants aged 2 years or younger with fever without source (55 [100%] of 55 vs 41 [75%] of 55; p=0·0002) or with sepsis-like disease (16 [100%] of 16 vs nine [56%] of 16; p=0·008). Detection of enterovirus was less frequent in blood than in CSF of patients with suspected meningitis (165 [67%] of 246 vs 222 [90%] of 246; p<0·0001).Interpretation Testing for enterovirus in blood by PCR should be an integral part of clinical practice guidelines for infants aged 2 years or younger. This testing could decrease the length of hospital stay and reduce exposure to antibiotics for low-risk patients admitted to the emergency department with febrile illness.Funding University Hospital Clermont-Ferrand.

Enterovirus, parechovirus, adenovirus and herpes virus type 6 viraemia in fever without source

“…Other studies have shown that the HEV prevalence in the plasma of children <3 months old with fever was similar to our cohort, ranging from 14.5% to 16.7%,18 19 or 24% after excluding patients with positive bacterial cultures 20. Similarly, a recent multicentre study found that the prevalence of HEV in the blood of children <2 years old presenting with FWS, sepsis or suspected meningitis, and enrolled between June and October, was 35.2% 21. This was in line with our findings when considering that their enrolment only happened during the peak HEV season.…”

“…This confirms previous findings showing that viraemia is rare in afebrile children6 23 and emphasises the fact that viraemia is not an incidental finding. Although viral shedding in stool or NPS is frequent, there is no evidence of shedding in the plasma after active infection, confirming that our findings reflect an active infection 21 23–25. Similarly, even though herpesvirus microRNAs can be detected in the plasma during latency,26 there is no evidence that HHV-6 DNA can be detected in the absence of active infection 27.…”

“…Second, the relative risk of an SBI was lower among patients with viraemia than among patients without documented viraemia. Third, coinfection involving more than one virus in the blood was rare in our cohort, as was coinfection with different viruses in other compartments, as previously shown for HEV-infected infants and neonates 21. The prevalence of viraemia was also significantly lower in a cohort of children <3 years old who presented to dental or fracture clinic compared with our cohort of children with FWS.…”

Screening for enteroviral meningitis in infants and children—Is it useful in clinical practice?

“…Testing for older children depends on CSF pleocytosis or if specifically requested by consultant pediatricians. The value of undertaking EV PCR on blood samples to minimize the necessity for taking LPs is also being reviewed as it has recently been showed to have importance as an additional screening test . Most cases occur in healthy infants with nonsevere infection.…”

“…8 The value of undertaking EV PCR on blood samples to minimize the necessity for taking LPs is also being reviewed as it has recently been showed to have importance as an additional screening test. 13 Most cases occur in healthy infants with nonsevere infection. However, consideration should also be given if presenting more acutely unwell with unusual complications, particularly given the potential for changing epidemiology, outbreaks and/or more pathogenic EV strains (eg EV D68/71).…”