Accepted Manuscript Title: Epidemiology and Clinical Outcomes of Viral Central Nervous System Infections Authors: Fatma Ben Abid, Mohammed Abukhattab, Hafedh Ghazouani, Obada Khalil, Ahmed Gohar, Hussam Al Soub, Muna Al Maslamani, Abdullatif Al Khal, Eman Al Masalamani, Said Al Dhahry, Samar Hashim, Faraj Howadi, Adeel A. Butt PII: DOI: Reference:
S1201-9712(18)34442-4 https://doi.org/10.1016/j.ijid.2018.06.008 IJID 3262
To appear in:
International Journal of Infectious Diseases
Received date: Revised date: Accepted date:
24-12-2017 31-5-2018 11-6-2018
Please cite this article as: Abid Fatma Ben, Abukhattab Mohammed, Ghazouani Hafedh, Khalil Obada, Gohar Ahmed, Soub Hussam Al, Maslamani Muna Al, Khal Abdullatif Al, Masalamani Eman Al, Dhahry Said Al, Hashim Samar, Howadi Faraj, Butt Adeel A.Epidemiology and Clinical Outcomes of Viral Central Nervous System Infections.International Journal of Infectious Diseases (2018), https://doi.org/10.1016/j.ijid.2018.06.008 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
1 Epidemiology and Clinical Outcomes of Viral Central Nervous System Infections
Fatma Ben Abid1, Mohammed Abukhattab1, Hafedh Ghazouani5, Obada Khalil1, Ahmed Gohar1, Hussam Al Soub1,2, Muna Al Maslamani1,2, Abdullatif Al Khal1,2, Eman Al Masalamani3, Said Al
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Dhahry4, Samar Hashim1, Faraj Howadi1, Adeel A. Butt1,2
Department of Medicine, Division of Infectious Diseases, Hamad Medical Corporation, Doha,
Qatar
Weill Cornell Medical College, New York, NY, USA and Doha, Qatar
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Department of Pediatrics, Division of Infectious Diseases, Hamad Medical Corporation, Doha,
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Qatar
Department of Laboratory Medicine and Pathology, Section of Virology and Molecular Biology,
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Hamad Medical Corporation, Doha, Qatar 5
Department of Bioinformatics, Department of Medical Oncology, National Center for Cancer Care
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and Research, Hamad Medical Corporation, Doha, Qatar
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Address for correspondence:
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Fatma Ben Abid, MD, MRCP, SCE ID, SCE chest Department of Medicine
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PO Box 3050 Doha, Qatar
Email:
[email protected]
2 Highlights (for review)
Among 7,690 patients with available CSF results, 550 cases met the inclusion criteria (meningitis 75%; encephalitis 25%).
Viral etiology was confirmed in 38% (enterovirus, 44%; Epstein-Barr virus, 31%; varicella zoster virus, 12%). Our results showed that EBV was the leading pathogen among cases of
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encephalitis. We couldn’t find other associated causative pathogens or underlying
comorbidities in our patients. The climate and heterogeneity of our population might be the explanation of this new trend.
Antibiotics and acyclovir are overly used even when a viral etiology is confirmed. There is a need for clinician education regarding etiology and treatment of viral
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CNS infections. This will have further implication on antimicrobial stewardship to
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prevent unnecessary use of antibiotics and antivirals and consequently prevent
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further resistance.
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Abstract:
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Background: Central nervous system (CNS) viral infections are an important cause of morbidity and mortality. No data are available regarding their epidemiology in Qatar.
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Design: We retrospectively evaluated all cerebrospinal fluid findings from January 2011 – March 2015 at Hamad Medical Corporation. Those with abnormal CSF finding were included in our study.
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We excluded those with missing medical records, no clinical evidence of viral CNS infection or proven bacterial, fungal or tuberculosis CNS infection. CNS clinical findings were classified as
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meningitis, encephalitis or myelitis. Results: Among 7,690 patients with available CSF results, 550 cases met the inclusion criteria (meningitis 74.7%; encephalitis 25%; myelitis 0.4%). Two-thirds (65%) were male and 50% were between 16-60 years old. Viral etiology was confirmed in 38% (enterovirus, 44.3%; Epstein-Barr
3 virus, 31%; varicella zoster virus, 12.4%). The estimated incidence was 6.4 per 100,000 population. Two persons died and the rest were discharged to home. Among those with confirmed viral etiology, 83.8% received ceftriaxone (mean duration 7.3+5.2 days), 38% received vancomycin
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(mean duration 2.7+5.4 days) and 38% received at least one other antibiotic. Intravenous acyclovir was continued for more than 48 hours in patients with confirmed negative viral etiology (mean duration 5+5.6 days).
Conclusion: Viral etiology is not uncommon among those evaluated for CNS infection in Qatar.
Clinical outcomes are excellent in this group of patients. Antibiotics and acyclovir are overly used
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even when a viral etiology is confirmed. There is a need for clinician education regarding etiology
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and treatment of viral CNS infections.
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Keywords: Viral central nervous system; infection; meningitis;encephalitis; meningoencephaltitis; myelitis; enterovirus; herpes simplex, type 1 and 2; varicella zoster virus; cytomegalovirus; Epstein
Background:
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Barr, virus.
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Viral infections of the central nervous system (CNS) including meningitis, encephalitis and myelitis
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are commonly seen in clinical practice worldwide [1]. In particular, viral meningitis is among the most common CNS infections, which accounts for the majority of cases of total viral CNS
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infections. Encephalitis and myelitis, on the other hand, are much less common [2,3]. The incidence differs by geography, age groups, case definition and research method [4,5,6]. The estimated annual incidence of all viral causes of encephalitis worldwide is 10.5 per 100,000 in children, 2.2 per 100,000 for adults and 6.34 per 100,000 for all ages [7, 8, 9]. The mortality from viral encephalitis ranges from 3.8% to 7.4% [10, 11]. However, most cases of viral CNS infection
4 and patients may not seek care or undergo a diagnostic lumbar puncture. Therefore, the reported incidence may underestimate the true incidence of this condition [12].
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The assessment of patients with probable viral CNS infections is complicated by lack of standardized case definition, large number of viruses that may cause such infections and relatively
limited diagnostic tools [13]. Enteroviruses are by far the most common pathogens involved in
viral meningitis (85-90% from all viral causes) in the western, and south Asian countries respectively [14,15,16]. Herpes viruses, including HSV1/HSV2, varicella zoster virus, are also well
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known causes of viral meningitis and encephalitis worldwide [17]. Enteroviruses exhibit a marked
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seasonality with specific geographical predilections. Hence, an accurate travel history is very
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important. Viral CNS infections are usually self-limiting, but in children less than 1 month old, and
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in immunocompromised patients, the infection can be more serious. Some infected patients may develop serious sequelae, such as long-term cognitive impairment, short term memory loss,
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psychiatric morbidity and chronic fatigue syndrome [18,19,20].
While there have been significant developments in the diagnostic methods for rapid, accurate,
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and early identification of the causing viruses, no major breakthroughs in the treatment of viral
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meningitis have been reported. Efforts aimed at early identification of the causative viruses are
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critical for optimal clinical management of patients with viral encephalitis [21].
The primary objectives of this study were to determine the etiology, clinical and laboratory characteristics and outcomes of persons admitted with CNS viral infections in Qatar. We also sought to assess the magnitude of inappropriate use of antibiotics in patients with viral CNS infection.
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Material and methods: Study design
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We conducted a retrospective descriptive study that included all admitted patients who underwent a lumbar puncture and CSF analysis for possible CNS infection at Hamad Medical Corporation (HMC) between January 2011 and March 2015. HMC is the principal and the largest
public sector healthcare provider in the State of Qatar, providing over 85% of inpatient bed
capacity in the State of Qatar. HMC also houses the National Virology Laboratory which serves as
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reference laboratory for viral isolates for the whole State of Qatar.
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Study Population
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To identify persons with viral CNS infection, we screened all cerebrospinal fluid (CSF) samples sent
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to our National Virology Laboratory for viral polymerase chain reaction (PCR) between January 2011 and March 2015. The flowchart of the study was summarized in figure 1. All CSF samples
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were reviewed for chemistry, cell count and differential, bacterial, fungal and TB cultures and viral
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PCR analysis by two members of the study team. We included only patients with positive CSF sample that was sent at the suspicion of CNS infection. A positive CSF was defined as having any
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of the following: CSF white blood cells (WBC) 5 or more cells/mm3, protein more than 0.4 gm/dL,
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or positive viral PCR supplementary table 1. For duplicate samples on the same person, only the first CSF was counted. Medical records were reviewed by two members of the study team.
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Patient’s demographics, clinical characteristics, laboratory test results, imaging, treatment and outcomes were retrieved. Imaging results for computerized tomography (CT) scan and magnetic resonance imaging (MRI) of the brain and electroencephalograms (EEG) were reviewed and classified as normal or abnormal based on criteria listed in supplementary table 2. We classified the cases into three clinical syndromes including meningitis , encephalitis and myelitis. Case
6 definitions for these syndromes are provided in supplementary table 1. Patients with positive CSF for bacterial/fungal/tuberculosis cultures were excluded.
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Viral diagnostics: The test method used was Fast Track Diagnostics viral meningitis qualitative multiplex Real-Time
PCR assay on ABI 5700 analyzer. The nucleic acids were automatically extracted and processed in a multiplex PCR assay for enterovirus (EV), herpes Simplex virus type 1 and 2 (HSV1/HSV2),
varicella virus (VZV), cytomegalovirus (CMV), Epstein-Barr virus (EBV), mumps, adenovirus and
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parechovirus. PCR was done for all CSF.
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Statistical methods:
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Descriptive statistics were used to summarize demographic, epidemiological, clinical and laboratory characteristics of the patients. Mean and standard deviation (SD) were described for
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the continuous variables with normal distribution and ranges for the continuous variables with
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skewed distribution. Frequencies and proportions were used for categorical variables. A P-value of 0.05 or less was considered significant. We used STATA version 12.0 (Statacorp, College Station,
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TX) for exploratory data analysis and descriptive statistics.
Ethical Considerations:
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The study was approved by the Institutional Review Board at Hamad Medical Corporation. A waiver for the requirement to get an informed consent was granted due to the retrospective nature of data collection and analysis.
7 Results: We screened 7,690 CSF samples that were sent to our National Virology Laboratory from January 2011 to March 2015. Of these, 2,160 were positive per our definition. Medical records were
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available for 1,650 persons and 550 cases met our case definition for acute viral CNS infection in supplementary table 1. [32] All patients identified were acute admissions through adult and pediatric emergency room. No patients had more than one episode during the study period.
Baseline demographic and clinical characteristics are summarized in table 1. The mean age +SD was 20.5+18.9 years, 65% were male and 81% were non-Qatari nationals. Travel history was
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documented for 391 persons, of whom 87 (16%) had traveled outside of Qatar in one month
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preceding their illness. Contact with a sick person was reported in 70 patients (13%). Twenty-eight
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cases (5%) had diabetes mellitus and one person was on immunosuppressive medication. Of the
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550 cases that met our definition of viral CNS infection, 411 (74.7%) were classified as meningitis, 137 (25%) as encephalitis, and 2 (0.4%) as myelitis. Fever was the most common reported
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symptom (85%), followed by headache (54%), vomiting (50%), nausea (33%), reduced
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feeding/appetite (32%), altered mental status (32%), seizures (17%) and diarrhea (13%). The most common signs were fever (48%), neck rigidity (39%), Kernig’s sign (17%), Brudzinzski’s sign (11 %),
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skin rash (7%), cranial nerve palsy (1.5) and spastic or flaccid paralysis (0.4%) table 1.
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The mean CSF protein level was 0.72+/-0.67 in meningitis, 0.74+/-0.74 in meningoencephalitis, 0.78+/-0.49 in encephalitis and 0.78+/-0.66 in myelitis. The mean CSF WBC was 110+/-366.5 in
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meningitis, 43.5+/-145 in meningoencephalitis, 78+/-98 in encephalitis and 78+/-391 in myelitis. Computed tomography (CT scan) was performed in 372 (68%) cases and at least one positive finding was reported in 88 (24%) cases. Magnetic resonance imaging (MRI) of the brain was performed in 176 (32%) cases, with a positive finding reported in 99 (56%) cases. Electroencephalogram (EEG) was done in 65 cases and 32 (49%) had positive changes.
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Etiology of viral CNS infections by syndrome is provided in table 2. A definitive viral etiology was found in 210 (38%) of all CNS syndromes. For cases of meningitis, 160 (39%) cases had positive
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virus in CSF, encephalitis 49 (36%)and myelitis 1 (50%). The most common viral pathogens identified for each clinical syndrome by age group are presented in supplementary table 3. The monthly distribution of CNS infection was noted to be higher in the month of December, followed
by February and May 13%, 11%, 10% respectively. Enterovirus cases were noted to be higher in December (14%) figure 2.
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Ninety-eight per cent of persons with viral CNS infection were admitted to the medical ward
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(mean duration of stay 7.8+6.4 days) and 2% to the intensive care unit (mean duration of stay
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2.7+5.4 days). Among those with confirmed viral etiology, 83.8% received ceftriaxone (mean
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duration 7.3+5.2 days), 38% received vancomycin (mean duration 2.7+5.4 days) and 38% received at least one other antibiotic. Intravenous acyclovir was continued for more than 48 hours in
Discussion:
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patients with confirmed negative viral etiology (mean duration 5+5.6 days) figure 3.
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We describe the epidemiology, clinical characteristics and clinical outcomes of patients with viral
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CNS infections in Qatar. The population was young with a male predominance similar to those in earlier studies [15,17,22,23]. Younger age and male predominance may at least partly be
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explained by the demographics of Qataris population, which consists of >80% expatriates, with a large number being single male workers. In our study the calculated annual incidence for viral CNS infection was 6.4 per 100,000 which were similar to those reported previously in the literature. For instance, the range of reported incidence of suspected viral CNS infection is wide ranging from 0.7 to 100 patients/100,000 person’s year [7,8,9,24,25,26]. This broad range was explained by the
9 differences in geographic distribution, population studied and case definition [4,5,6]. In our study the seasonal distribution of viral CNS infections mirrors the incidence of enteroviruses, with small peaks in February, June and December
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Viral CNS infections are challenging to diagnose despite the advances in diagnostic techniques. Up to 80 % of the cases remain of unknown etiology [17]. In our study a definite pathogen was
confirmed in 38% of the cases. A higher percentage of confirmed etiology has been reported mainly in prospective studies that used multiple methods to identify the etiology of viral CNS. For
instance, Kupila et al used PCR analysis from CSF and blood as well as viral culture and serology
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from CSF to diagnose cases. In our study we only used PCR analysis which might explain the lower
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number of confirmed pathogen.
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The leading causes of viral meningitis worldwide in all age group were human enteroviruses
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[15,16,22,23,27,28]. On the other hand, the viral etiology of encephalitis differs from one geographic area to another. For instance, HSV was the leading pathogen of viral encephalitis in
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France, England, Spain and USA [22, 27,28], while enteroviruses were the leading cause in China
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[23]Japanese encephalitis and dengue virus were the most common viral etiology for viral CNS infection in Vietnam [17]. A variety of EBV related CNS infection (either primary infection or
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reactivation) have been reported in literature. To our knowledge, the dominant role of EBV has
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not been recognized earlier. It was demonstrated previously that EBV reactivation and coinfection was mostly triggered by echovirus [29,30]. One large study done in pediatric population over 10-
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year period found that a positive EBV in CSF was mostly found together with other microbial findings in CSF of immunocompromised patients [31]. It is well known that EBV can reactivate in the setting of severe disease. For instance, Matthew et al reported that 53% of patients with bacterial meningitis had EBV reactivation and mortality was associated with higher CSF EBV load when adjusted for HIV [33]. Our results showed that EBV was the leading pathogen among cases
10 of encephalitis. We couldn’t find other associated causative pathogens or underlying comorbidities in our patients as we already excluded associated culture positive bacterial CNS infection. The climate and heterogeneity of our population might be the explanation of this new
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trend. Viral CNS infections are usually self-limiting, but in extreme ages and in immunocompromised patients, the infection can be more serious. Serious complications only reported in patients with
chronic enterovirus meningitis in patients with agammaglobulinaemia, hydrocephalus with lymphocytic choriomeningitis virus [18,19,20]. None of our patient had these conditions. Some
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infected patients may develop serious sequelae, such as long-term cognitive impairment, short
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term memory loss and chronic fatigue syndrome [20]. The case fatality rate and neurologic
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sequelae in encephalitis are usually related to the type of virus, underlying patient’s
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comorbidities, and timing from diagnosis to start of appropriate treatment (for HSV encephalitis). The clinical outcome in our study was overall good, only 2 cases died and the rest were discharged
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to home. Ninety-eight per cent were admitted to the medical ward and 2 % to an intensive care
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unit. The good prognosis noted in our encephalitis cases might be explained by the fact that the numbers of patients with HSV were very small and most of our patients were young and
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immunocompetent.
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We noted a high rate of use of antibacterial and antiviral agents even after a non-bacterial or nonHSV etiology was confirmed. This has the potential of drug toxicity, higher costs and development
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of increased antimicrobial resistance. Our study has several limitations. It is a retrospective study and we were not able to review all the files of patients with suspected viral CNS infection which would have given us more information and perform more extensive analytical analysis. We included only patients who underwent lumbar puncture and CSF PCR, which may miss potential cases with milder infection
11 thus underestimating the true incidence of viral CNS infections. In addition, we didn’t have arboviral serologies for our patients.
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In conclusion, we have shown that viral etiology is not uncommon among those evaluated for CNS infection in Qatar, and is most commonly seen in adult population originally from Southeast Asian immigrants. Enteroviruses are more prevalent in children with meningitis, in contrast EBV were more common in adults with encephalitis. Clinical outcomes are generally excellent in this group
of patients. Antibiotics and acyclovir are overly used even when a non-HSV viral etiology is
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confirmed. There is a need for clinician awareness and further education regarding etiology and
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treatment of CNS infections.
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Conflict of interest statement:
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All authors have no conflict of interest to declare.
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Ethical Approval:
The study was approved by the Institutional Review Board at Hamad Medical Corporation. A
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waiver for the requirement to get an informed consent was granted due to the retrospective
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nature of data collection and analysis.
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Funding Source: Medical Research Center at Hamad Medical Corporation
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Infectious Diseases. 2011 Nov 9;205(1):106-10.
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Figure 1. Study flow sheet.
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Fig 2. Seasonal distribution of viral (0verall) and enterovirus central nervous system infections in Qatar.
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Fig 3. Duration of antibiotic and antiviral therapy for viral central nervous system infections.
18 Table 1. Demographic and clinical characteristics of persons with viral central nervous system infections.
N (%)
Male sex Qatari nationality Mean age +/- Sd
