Original article Arch Dis Child: first published as 10.1136/archdischild-2019-317382 on 28 August 2019. Downloaded from Enterovirus, parechovirus, adenovirus and herpes virus type 6 viraemia in fever without source Arnaud Gregoire L’Huillier, 1,2 Chiara Mardegan,3 Samuel Cordey, 2 Fanny Luterbacher,4 Sebastien Papis,3 Florence Hugon,4 Laurent Kaiser,2 Alain Gervaix,4 Klara Posfay-Barbe,1,2 Annick Galetto-Lacour4 ► Additional material is ABSTRACT What is already known on this topic? published online only. To view Objectives To evaluate the potential associations please visit the journal online between fever without a source (FWS) in children (http:// dx. doi. org/ 10. 1136/ Although only 10%–25% of cases are due to and detection of human enterovirus (HEV), human ► archdischild- 2019- 317382). serious bacterial infections, the rest are likely parechovirus (HPeV), adenovirus (AdV) and human 1Pediatric Infectious Diseases due to common viruses. herpesvirus type 6 (HHV-6) in the plasma; and to Unit, Department of Child and Fever without source is a frequent cause of assess whether the detection of viruses in the plasma ► Adolescent Medicine, Geneva paediatric consultations, requiring invasive University Hospitals and Medical is associated with a reduced risk of serious bacterial investigations, hospital admission and School, Geneva, Switzerland infection (SBI) and antibiotic use. 2Division of Infectious Diseases administration of empirical antibiotics. Design and setting Between November 2015 and Laboratory of Virology, Division of Laboratory Medicine, and December 2017, this prospective, single-centre, Geneva University Hospitals diagnostic study tested the plasma of children <3 years and Medical School, Geneva, old with FWS. Real-time (reverse-transcription) PCR for What this study adds? Switzerland HEV, HPeV, AdV and HHV-6 was used in addition to the 3Division of General Pediatrics, Department of Child and standardised institutional work-up. A control cohort was ► Viraemia is frequent during fever without Adolescent Medicine, Geneva also tested for the presence of viruses in their blood. source and associated with similar antibiotic University Hospitals and Medical Results HEV, HPeV, AdV and HHV-6 were tested for in use despite a fivefold lower risk of serious School, Geneva, Switzerland 4 the plasma of 135 patients of median age 2.4 months bacterial infection. Division of Pediatric old. At least one virus was detected in 47 of 135 Emergencies, Department of ► Point-of-care PCR testing for viruses in the Child and Adolescent Medicine, (34.8%): HEV in 14.1%, HHV-6 in 11.1%, HPeV in 5.9% blood could potentially reduce admission rates Geneva University Hospitals and AdV in 5.2%. There was no difference in antibiotic and antibiotic use. and Medical School, Geneva, use between patients with or without virus detected, Switzerland despite a relative risk of 0.2 for an SBI among patients with viraemia. Controls were less frequently viraemic reduce unnecessary invasive investigations, hospital Correspondence to than children with FWS (6.0% vs 34.8%; p<0.001). Dr Arnaud Gregoire L’Huillier, admissions and antibiotic administration. Geneva University Hospitals, Conclusions HEV, HPeV, AdV and HHV-6 are frequently Four ubiquitous viruses have been shown to play http://adc.bmj.com/ Geneva 1211, Switzerland; detected in the plasma of children with FWS. Antibiotic a predominant role in FWS: human enterovirus arnaud. lhuillier@ hcuge. ch use was similar between viraemic and non-viraemic (HEV), human parechovirus (HPeV), adenovirus patients despite a lower risk of SBI among patients with 6 These data have been presented (AdV) and human herpesvirus type 6 (HHV-6). as an oral presentation at viraemia. Point-of-care viral PCR testing of plasma might HEV and HPeV are RNA viruses which have a the 2018 Infectious Diseases reduce antibiotic use and possibly investigations and seasonal summer pattern in the northern hemi- Society of America (IDSA) admission rates in patients with FWS. sphere,7 8 whereas AdV and HHV-6 are DNA annual meeting (IDweek) in San Trial registration number NCT03224026. viruses with yearly circulation.9 10 All these viral on September 30, 2021 by guest. Protected copyright. Francisco, USA. infections can present as sepsis or FWS in children 8–12 Received 8 April 2019 of all ages, although HPeV is diagnosed mainly 8 Revised 29 July 2019 INTRODUCTION in infants <3 months old. Because of the frequent Accepted 7 August 2019 Fever without a source (FWS) is defined as a fever asymptomatic respiratory or enteral carriage of 13–15 for which neither an extensive medical history nor a these viruses, using nasopharyngeal or stool clinical examination can identify a cause.1 Although specimens is suboptimal for determining their role most children <3 years old presenting with FWS in FWS. Consequently, our study aimed to assess have a self-limiting viral infection, up to 10%–25% how often HEV, HPeV, AdV and HHV-6 viraemia have a serious bacterial infection (SBI).1–3 Therefore, were detected in children <3 years old presenting © Author(s) (or their many children require diagnostic laboratory tests to with FWS and whether patients with viraemia employer(s)) 2019. No identify the few patients with an SBI.1 4 5 Besides differed from non-viraemic patients in terms of commercial re-use. See rights clinical presentation, rates of SBI and management. and permissions. Published blood tests, more invasive laboratory procedures, by BMJ. such as lumbar puncture and urinary catheterisa- tion, are often required, followed by the empirical PTIA ENTS AND METHODS To cite: L’Huillier AG, Study design Mardegan C, Cordey S, et al. administration of broad-spectrum antibiotics, espe- Arch Dis Child Epub ahead of cially to younger patients who have an increased Participants for this prospective, single-centre, print: [please include Day risk of an SBI and often a non-specific clinical epidemiological diagnostic study were enrolled in Month Year]. doi:10.1136/ presentation.1 4 5 Consequently, identifying systemic the emergency room (ER) division of the Geneva archdischild-2019-317382 viral infections in this population could potentially University Hospitals. Inclusion criteria were (1) L'Huillier AG, et al. Arch Dis Child 2019;0:1–7. doi:10.1136/archdischild-2019-317382 1 Original article Arch Dis Child: first published as 10.1136/archdischild-2019-317382 on 28 August 2019. Downloaded from clinical diagnosis of FWS defined as a temperature of ≥38°C Clinical presentation, physical examination or laboratory measured at home or in the ER in acutely ill children <3 years investigations old with no identified focus of infection after a thorough history There were no significant differences in demographics between and clinical exam; and (2) <7 days of fever. Exclusion criteria virus-positive and virus-negative patients (table 1). Moreover, were (1) unavailable blood; and (2) comorbidities predisposing there were no differences in clinical presentations or findings to infections using chart review (cancer, primary or secondary between the groups, except for a faster respiratory rate in immunodeficiency, and iatrogenic immunosuppression). virus-negative patients (p=0.038). There were also no signifi- cant differences in the diagnostic investigations performed on Study specimen collection the two groups (table 1). The breakdown of clinical presentation Besides usual blood investigations for the normal clinical care of by virus is detailed in online supplementary table 1. children <3 years old presenting with FWS, plasma was tested by real-time reverse-transcription (RT)-PCR for HEV and HPeV, Initial laboratory results and management as well as real-time PCR for AdV and HHV-6 (online supple- Virus-positive patients had lower leucocyte (p<0.001), neutro- mentary methods). phil (p=0.002), lymphocyte (p<0.001) and C reactive protein values (p=0.013) than virus-negative patients (table 2). Definitions After medical history, clinical examination and initial labo- For the study’s purposes, the virus-positive group included ratory results, the anticipated risk of SBI was higher among patients with either HEV, HPeV, AdV or HHV-6 detected in virus-negative patients (p=0.029). Moreover, virus-positive their plasma, whereas the virus-negative group included patients patients were less likely to be admitted (p=0.006) and those with negative RT-PCR results. SBIs included documented bacte- admitted had shorter lengths of stay (p=0.048). However, there raemia requiring antibiotic treatment (blood cultures interpreted was no difference between the two groups in the likelihood of as contaminants were not considered as SBI), bacterial menin- receiving antibiotics, taking into account that physicians were gitis, osteomyelitis, pneumonia or urinary tract infection (UTI) blinded to viral RT-PCR results. Among patients who did receive (online supplementary methods). antibiotics, virus-positive patients were more likely to be treated with oral antibiotics (p=0.001) and had shorter durations of therapy (p=0.003) (table 2). Control group To confirm that viraemia was not an incidental finding, we performed real-time RT-PCR for HEV, HPeV, AdV and HHV-6 SBIs were rare among patients with viraemia on the serum of 50 control children <3 years old consulting at Twenty study patients (14.8%) were diagnosed with an SBI. dental or fracture clinics, and enrolled through the Canadian One patient had Haemophilus influenzae (type f) bacteraemia Laboratory Initiative on Paediatric Reference (CALIPER) study