Enteroviruses (EVs) and human parechoviruses (HPeVs) are important pathogens that cause fever in young infants and meningitis in children and have similar clinical symptoms and characteristics. The aim of this study was to compare the clinical symptoms and characteristics of EV and HPeV infections in young children and infants.
From June to August 2018, we obtained 50 cerebrospinal fluid (CSF) samples, of which 36 and 14 were EV- and HPeV-positive, respectively, as determined by film array methods. We then compared the clinical characteristics and laboratory values of patients with EV and HPeV infections.
HPeV patients had a lower age than EV patients, but had similar sex predominance and fever duration. Moreover, EV patients had a higher prevalence of headache and mannitol use than HPeV patients. The blood and CSF white blood cell counts were lower among HPeV patients even after adjusting for sex and age. Furthermore, both viruses were found to cause occasional transient white matter injuries in the brain.
The clinical characteristics of HPeV and EV infections were found to be generally similar, but with a few noteworthy differences.
Aseptic meningitis is commonly caused by enterovirus (EV) infection, which is mostly a benign pathogen with a few exceptions in all ages, especially in children [
Both EV and HPeV infections have similar clinical findings and are the main leading causes of meningoencephalitis (ME) in neonates, and can sometimes cause fatal diseases, especially in infants and neonates. EV infections, especially those of the E71 virus, have been reported to be fatal in children, with few cases of endemic encephalitis and brain stem encephalitis. Recently, HPeV has also been reported to cause white matter disease in neonates with some cases being fatal [
This study aimed to compare the clinical aspects of EV and HPeV infections. Moreover, the findings of this study will help to better manage patients and their treatment and inform future studies.
This retrospective chart review study was performed on children who underwent cerebrospinal fluid (CSF) examination in the CHA Bundang Hospital for ME diagnosis due to fever or neck stiffness symptoms from 1st June 2018 to 31st August [
We retrospectively reviewed the medical records of the HPeV- and EV-positive patients and collected data such as age, sex, symptoms (e.g., duration of fever, presence of vomiting, headache, and irritability), and treatment (e.g., administration of hypertonic fluid [mannitol] and immunoglobulin). Furthermore, we collected their laboratory results such as hemoglobin, white blood cell (WBC) count and its differential count, platelet count, and erythrocyte sedimentation rate (ESR) as well as CSF examination findings such as CSF total and differential WBC count, pH, protein levels, and glucose. Subsequently, we adjusted the findings according to age and sex. Lastly, we collected and analyzed brain scan images where available. The CSF WBC was corrected according to the CSF red blood cell (RBC) count if the CSF RBC count was more than 50,000 cells/mm3. In cases where the CSF WBC count was more than 10 cells/mm3, we used the differential WBC count. In cases where the patient underwent multiple lab tests, such as for C-reactive protein (CRP) and WBC count, the highest values were used for statistical evaluation.
We assessed the CSF samples for the viruses using the Film Array® ME panel from bioMerieux, which requires 200 μL of CSF and takes about an hour to complete. We used freeze-dried reagents to detect the nucleic acids of the particular pathogens. This method allowed detection of all species of EV (A–D) and several serotypes of human EV including EV71, EV68, coxachieviruses, and echoviruses. Moreover, it allowed detection of HPeV serotypes 1–6 [
Data were analyzed using the chi-square test, Fisher’s exact t-test, Mann-Whitney test, and multiple logistic or linear regression using SPSS version 23.0 (IBM Co., Armonk, NY, USA). Multivariable regression models were used to estimate the adjusted odds ratios and 95% confidence intervals adjusted for age and sex. A
The study protocol was approved by the appropriate Institutional Review Board of CHA University (CHAMC-2018-08-011). Informed consent was waived by the board.
Samples from a total of 161 patients (males 96, females 65) were examined using film array-ME and 50 patients were positive for EV or HPeV infections (
There was no significant difference in the total fever duration between the EV and HPeV group (29.2 [IQR, 22.0 to 58.5] and 37.3 hours [IQR, 26.0 to 5.0], respectively;
The serum WBC count was higher in the EV group than in the HPeV group (10,851±3,064 vs. 5,366±31,953,
Regarding treatment, the use of hyperosmotic fluid (mannitol) was higher in the EV group (
One newborn (female, 40 days old) who tested positive for HPeV had seizures with unilateral semiology, with an electroencephalograph showing a negative sharp wave. Her CSF WBC count was only 2/mm3, and multifocal small hyperintensities were observed using diffusion-weighted magnetic resonance imaging (MRI) of the bilateral cerebral white matter (
Computed tomography (CT) scans were done in 18 EV-infected patients, five patients (three EV-infected, two HPeV-infected) underwent MRI, and three HPeV-infected patients underwent cranial ultrasonography. A total of 25 patients did not undergo brain imaging or electrophysiologic studies. Among those who underwent CT and cranial ultrasonography, none showed gross abnormalities, and a baby showed mild periventricular leukomalacia. Among the five patients who underwent MRI examination, two showed abnormal findings of high signal intensity on diffusion-weighted magnetic resonance images in the white matter of a relatively short duration that was fully reversible (
Both EVs and HPeVs belong to same viridae [
We found that the CSF WBC count was relatively low in the HPeV group compared with the EV group. Previous studies also reported a low CSF WBC in this group [
The age distribution, specifically the younger age preference of these viruses, as shown in this study, are possibly due to an actual age preference of the HPeVs [
Treatment of infants with IVIG may prevent brain viral infection from becoming fatal or severe sequelae [
This study has several limitations. As previously mentioned above, older children with mild symptoms did not undergo lumbar puncture, which possibly resulted in selection bias. An early CSF study can show a low WBC count, which then increased during the subsequent few days. Moreover, we did not perform MRI examinations on babies with neurologic symptoms or CT and cranial ultrasonography in children/babies with mild symptoms; therefore, we might have missed cases with white matter injury. Diffusion-weighted MRI image can detect white matter injury resulting from HPeV encephalitis [
We found that HPeV and EV infection have similar clinical characteristics and mostly similar laboratory values. However, we found between-group differences in the predominant age and CSF and blood WBC count with the CSF WBC count in HPeV patients being less than the cut-off value for aseptic meningitis. Therefore, we should consider assessing for viral infection even when the CSF WBC count is low. Lastly, MRI examination can help in the positive diagnosis of EV and HPeV infections, especially in infants.
No potential conflict of interest relevant to this article was reported.
Conceptualization: SR. Data curation: SR. Formal analysis: SR. Funding acquisition: SR. Methodology: SR. Project administration: SR. Visualization: SR. Writing-original draft: SR. Writing-review & editing: SR.
Flow diagram of the inclusion process of participants in this study. CSF cerebrospinal fluid; ME, meningoencephalitis; HHV6, human herpesvirus 6.
Magnetic resonance imaging scans of severe cases. (A) A 40-day-old female who had a fever with unilateral seizure tested positive for human parechovirus after CSF assessment. Multifocal small hyperintense lesions were transiently in the diffusion-weighted image of the bilateral cerebral white matter (including the corpus callosum splenium and in another image level and the bilateral perirolandic area and ventrolateral thalami in a later assessment) observable. (B) After 6 days, a follow-up study showed a slightly decreased signal with a small remnant. (C) A 46-day-old female who showed fever and was enterovirus-infected. A tiny, subtle high signal intensity was transiently in the diffusion-weighted image of the right side corpus callosum genu, observable. (D) After 6 days, an improved signal change was observed in the right corpus callosum genu. CSF, cerebrospinal fluid.
Demographic and clinical characteristics of children with enterovirus or human parechovirus infections with and without adjustment for age and sex
Characteristic | No. | Enterovirus (n=36) | Parechovirus (n=14) | OR (95% CI) | Adjusted for age and sex | ||
---|---|---|---|---|---|---|---|
aOR/B (95% CI) | |||||||
Clinical data | 36 | 14 | |||||
Age (mo) | 50 | 27 (3–77) | 2 (2–3) | 0.000 |
|||
Male sex | 50 | 19 (52.8) | 6 (42.9) | 0.754 |
0.671 (0.193 to 2.329) | ||
Symptom | |||||||
Fever | 50 | 34 (94.4) | 14 (100) | 0.368 |
1.412 (1.177 to 1.693) | 0.999 | 0.000 |
Fever duration above 38℃ (hr) | 50 | 29.2 (22.0–58.5) | 37.3 (26.0–53.0) | 0.713 |
0.632 | 4.306 |
|
Fever duration above 37.5℃ (hr) | 50 | 41.0 (24.5–84.7) | 50.3 (46.0–66.0) | 0.589 |
0.481 | 7.468 |
|
Vomiting | 50 | 12 (33.3) | 1 (7.1) | 0.058 |
0.154 (0.018 to 1.319) | 0.397 | 0.365 |
Headache | 50 | 15 (41.7) | 0 | 0.004 |
0.600 (0.458 to 0.786) | 0.999 | 0.000 |
Irritability | 50 | 2 (5.6) | 0 | 0.368 |
0.708 (0.591 to 0.849) | 0.998 | 0.000 |
ICP (cmH2O) | 17 | 14.35±8.46 | |||||
Laboratory findings of serum samples | |||||||
WBC (/μL) | 50 | 10,851±3,064 | 5,366±1,958 | 0.015 |
0.000 | –5,275.6 |
|
Seg (%) | 50 | 66.5 (38.2–84.5) | 55.0 (43.0–64.0) | 0.510 |
0.004 | 14.973 |
|
CRP (mg/dL) | 50 | 0.32 (0.08–0.90) | 0.22 (0.09–0.62) | 0.634 |
0.946 | –0.019 |
|
Procalcitonin (ng/mL) | 29 | 0.09 (0.07–0.10) | 0.12 (0.09–0.19) | 0.028 |
0.093 | 0.125 |
|
Hemoglobin (g/dL) | 50 | 12.1±1.1 | 11.2±2.7 | 0.236 |
0.638 | –0.256 |
|
Platelet (103/μL) | 50 | 365±108 | 385±113 | 0.557 |
0.322 | –34.560 |
|
ESR (mm/hr) | 20 | 13 (10–28) | 13 (6–18) | 0.484 |
0.941 | –0.722 |
|
Laboratory findings of CSF samples | |||||||
pH | 50 | 7.5 (7.0–7.5) | 7.5 (7.0–7.5) | 0.481 |
0.639 | –0.060 |
|
RBC (/mm3) | 50 | 3 (1–35) | 1 (0–173) | 0.199 |
0.577 | –1,347.6 |
|
WBC (/mm3) | 50 | 30 (4–153) | 2 (1–5) | 0.001 |
0.018 | –259.5 |
|
Seg (%) | 21 | 31.3±25.6 | |||||
Protein (mg/dL) | 50 | 42.8±21.7 | 47.9±15.1 | 0.426 |
0.552 | –3.837 |
|
Glucose ratio (CSF/serum) | 50 | 0.57±0.09 | 0.56±0.08 | 0.606 |
0.621 | 0.015 |
|
Treatment | |||||||
IVIG | 50 | 8 (22.2) | 10 (71.4) | 0.002 |
8.750 (2.156 to 35.507) | 0.085 | 3.951 |
Manntiol | 50 | 17 (47.2) | 1 (7.1) | 0.009 |
0.443 | 5.047 |
Values are presented as median (interquartile range), number (%), or mean±standard deviation.
OR, odds ratio; CI, confidence interval; aOR, adjusted OR (adjusted with age and sex, reference value is enterovirus); B, coefficient; ICP, intracranial pressure; WBC, white blood cell count; seg, fraction of the segmented cell; CRP, C-reactive protein; ESR, erythrocyte sedimental rate; CSF, cerebrospinal fluid; RBC, red blood cell; IVIG, intravenous immunoglobulin.
Adjusted odds ratio with logistic regression analysis, fever duration 38°C and 37.5°C;
β With linear regression analysis;