- Email: [email protected]
Hospitalized Children With Encephalitis in the United States: A Pediatric Health Information System Database Study
Accepted Manuscript Hospitalized Children with Encephalitis in United States: A PHIS Database Study Dayanand Bagdure, MBBS MPH, Jason W. Custer, MD, Suchitra Rao, MD, Kevin Messacar, MD, Samuel Dominguez, MD PhD, Brandon W. Beam, JD, Adnan Bhutta, MBBS PII:
S0887-8994(16)30074-1
DOI:
10.1016/j.pediatrneurol.2016.04.014
Reference:
PNU 8902
To appear in:
Pediatric Neurology
Received Date: 10 February 2016 Revised Date:
29 April 2016
Accepted Date: 30 April 2016
Please cite this article as: Bagdure D, Custer JW, Rao S, Messacar K, Dominguez S, Beam BW, Bhutta A, Hospitalized Children with Encephalitis in United States: A PHIS Database Study, Pediatric Neurology (2016), doi: 10.1016/j.pediatrneurol.2016.04.014. 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.
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Hospitalized Children with Encephalitis in United States: A PHIS Database
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Study
Dayanand Bagdure MBBS MPH1, Jason W Custer. MD1, Suchitra Rao MD2, Kevin Messacar,
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MD2, Samuel Dominguez, MD PhD2, Brandon W Beam, JD3, Adnan Bhutta, MBBS1. Department of Pediatrics; Division of Pediatric Critical Care Medicine, University of Maryland
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School of Medicine, Baltimore, MD
Department of Pediatrics; Division of Infectious Diseases, University of Colorado School of
Medicine, Aurora, CO
Informatics, Arkansas Children’s Hospital, Little Rock, AR
Corresponding Author:
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Dayanand Bagdure MBBS MPH
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110 S Paca St 8th Floor Baltimore MD 21202
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Phone No: 410-328-6957
Cell Phone No: 786-543-0577 Fax No: 410-328-0680
Email: [email protected]
Word Count: 2254
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Keywords: encephalitis, children, pediatric critical care, plasmapheresis Disclosure: Dr.Bagdure received funding from The PATIENTS program which is funded
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HS22135-01]. Other authors do not have any financial disclosures.
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through Agency for Healthcare and Research and Quality (AHRQ) [Grant Number: R24
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Abstract: Objectives: Given the paucity of data on resource utilization among children with encephalitis,
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the objective of the study is to describe the epidemiology, evaluate resource utilization, and discharge data of children with encephalitis admitted to United States hospitals from 2004-2013. Methods: We conducted a retrospective cohort study utilizing the Pediatric Health Information
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System (PHIS) database of children aged 0-18 years with ICD-9 codes for encephalitis from 2004-2013. Only the initial admissions were included and the age group analyzed was 0-18 years
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of age.
Results: Among 7298 children with encephalitis, 2933 (40%) were admitted to the PICU. The median age was 9 years and the overall median length of stay was 16 days, and children
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requiring critical care had median length of stay of 25 days. Children in the PICU were more likely to have seizures (<0.001) and head MRI imaging (<0.001) as compared to children on the floor. Similarly, children requiring critical care were more likely to have a broad diagnostic
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workup sent including CSF cultures, blood bacterial and fungal cultures, western equine encephalitis antibody, St. Louis Equine encephalitis antibody, varicella zoster serology, HIV 1
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antibody, HIV DNA PCR, Acid Fast stain, and lyme disease serology. 17% of children were treated with intravenous immunoglobulin (IVIG) and 4% underwent plasmapheresis. There was a trend of increasing use of IVIG and plasmapheresis in children with encephalitis over the studied period. 5944 (81%) of the children were discharged home and the mortality in this cohort was 3% (230). The mean charges for hospitalization for a child with encephalitis was $64604, and for those requiring critical care was $260012.
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Conclusions: Encephalitis is a significant cause of morbidity and mortality in children. Children with encephalitis admitted to the PICU are more likely have seizures, more extensive work up to determine the cause of encephalitis. Use of plasmapheresis and intravenous immunoglobulin
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(IVIG) is on a rise in hospitalized children. Prospective studies are necessary to better understand
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treatment and intervention strategies for children with encephalitis and their impact on outcomes.
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Introduction:
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Data regarding the health care burden of encephalitis in children remains unknown. The etiologies of encephalitis in children range from infectious (including bacterial, viral, fungal and parasitic diseases) to autoimmune processes1,2. Diagnosing the cause of encephalitis is often an
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exhaustive and expensive endeavor and even then 60% of the cases remain undiagnosed3.
Because of the varied etiologies, outcomes of encephalitis range from acute illness with rapid
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reversibility of symptoms to chronic debilitating conditions. Mortality though low, can be seen in infectious causes like herpes simplex encephalitis4.
Historically bacterial and viral encephalitis is discussed widely in literature with recent emphasis on antibody mediated encephalitis5. Even with comprehensive diagnostic evaluations using
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advanced diagnostic techniques, over 60% of cases of encephalitis remain without a clear etiology (California encephalitis study)6. In order to drive research into understanding the epidemiology and improving therapeutics for encephalitis, it is imperative to determine the
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hospital burden of encephalitis and the use of current therapies employed in children.
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Infectious Disease Society of America (IDSA) defines encephalitis as presence of an inflammatory process of the brain in association of clinical evidence of neurologic dysfunction 7. Encephalitis is either due to direct invasion of the central nervous system (CNS) or indirect involvement of the CNS8. Encephalitis is a histopathologic diagnosis, however brain biopsies are rarely performed due to their invasive nature. Consensus clinical diagnostic criteria have been published which evaluate clinical factors that suggest parenchymal inflammation, such as
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neuroimaging changes, electroencephalography changes, focal neurologic deficits and seizures9. In order to determine the causative agent cerebrospinal fluid analysis is performed in most cases. In addition, sampling of respiratory secretions, stool, and blood is conducted to look for
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pathogens associated with encephalitis at other sites. It is difficult to determine the significance of an infectious agent found outside of the CNS as the cause of encephalitis and often these are
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considered probable or possible causes.
As we continue to better recognize and understand immune mediated encephalitis (including
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anti-NMDA and other anti-neuronal antibodies), procedures like plasmapheresis and medications like intravenous immune globulin (IVIG) and immunomodulators are being utilized more frequently and earlier in the disease process10,11.
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Querying large administrative databases offer an opportunity to understand disease burden, report on trends of hospitalization and resource utilization, and evaluate outcomes. It also helps
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to understand the variation in management of diseases or disorders across numerous hospitals.
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Patients and Methods:
Data source
We retrospectively reviewed cases of encephalitis using the Pediatric Health Information System (PHIS)12. PHIS is a comprehensive pediatric database containing administrative and financial details for more than six million hospitalizations from 44 participating free standing children’s
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hospitals. The PHIS database includes patient demographic information, diagnoses and procedures data coded with International Classification of Diseases, 9th Revision (ICD-9) codes, resource utilization data, and outcome data. Data is extracted using ICD-9 codes, obviating the
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need for definitions for diagnoses. Data regarding laboratory investigations, medications,
imaging studies and other resource utilization data is coded under the Clinical Transaction
Classification (CTC) system (Truven Health Analytics, Ann Arbor, MI). Procedures are coded
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using both ICD-9 and CTC codes.
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The University of Maryland Institutional Review Board for the Protection of Human Subjects reviewed the study protocol and determined that this study does not fall under the jurisdiction of the Institutional Review Board review process.
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Study Population:
The study population was defined as all patients in the age group less than 18 years admitted to a
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PHIS participating hospital from 2004 – 2013 with a primary or secondary discharge diagnosis of encephalitis (ICD-9, 323, 323.01, 323.02, 323.1, 323.2, 323.4, 323.41, 323.42, 323.5, 323.51,
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323.52, 323.6, 323.61, 323.62, 323.63, 323.7, 323.71, 323.72, 323.8, 323.81, 323.82,323.9)13. Analysis was limited to first hospitalization only.
Data Collection:
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Data collection included demographic information, year of admission, source of admission, race and ethnicity, admission age and length of stay. We queried the data base for medication utilization including antibiotic and antiepileptic medications, imaging studies including imaging
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with CT, MRI; procedures including lumbar puncture, dialysis, mechanical ventilation and
plasmapheresis. Hospitalization charges for hospital stay and ICU stay were obtained. Outcomes
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data included mortality and disposition type (home, rehabilitation center).
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Statistical Analysis:
Descriptive statistics were calculated in Microsoft Excel 2007. Data are described with median and inter quartile range. Group differences were compared using chi-square tests for categorical variables and Mann-Whitney tests for continuously distributed variables. Statistical significance
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was defined as a p value < 0.05.
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Results
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Demographic data:
There were 7298 admissions for encephalitis during the years 2004-2013, of which 2933 (40%) were admitted to the intensive care unit. From 2004 to 2013 number of children with encephalitis increased from 593 to 847. The demographics of these patients are shown in Table 1. The median age at time of diagnosis was 9 years (IQR 3.8-13.3). Data on race was difficult to interpret as for over a third of the patient’s data on race was not reported. There were 230 deaths,
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and median length of hospital stay was 16 days (IQR 5-441). Of the cohort, 40% (2933) of the children were admitted to the PICU. Median length of stay in the PICU was 25 days.
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Procedures and Investigations:
4381 (60%) of children underwent lumbar puncture, 427 (14.5%) had an arterial line placed,
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1698 (58%) had a central line placed and 145 (5%) had tracheostomy in children admitted to the PICU. There were 41 (0.56%) children with encephalitis who received cardiopulmonary
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resuscitation during their hospital stay and 6 (<0.5%) children had pacemaker placed. 62 (2%) children had intracranial pressure monitoring device. Children admitted to the PICU (27%) were more likely to have seizures when compared to children admitted to the floor (12%) (p<0.0001).
Treatment data:
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Table 2 lists the investigations for these patients obtained from the database.
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Table 3 details the use of anti epileptics, anti-microbials and immunomodulators in this cohort. Over the 10 year period 2003-2014 there was increase in the number of patients receiving
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plasmapheresis and IVIG. Figure 1 shows the proportion of children admitted for encephalitis undergoing plasmapheresis. Figure 2 shows the proportion of children who received IVIG. Mean charges of hospitalization for a child with encephalitis on the floor was $64604 and in the PICU it was $260012. Table 2 shows the laboratory investigations and diagnostic procedures done on the cohort.
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Discussion:
We report the largest epidemiological study of inpatient children with encephalitis in the United
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States. Over a 10 year period there were increasing number of children being admitted with encephalitis and there was increase in the use of plasmapheresis and IVIG. Children with
encephalitis spend significant longer time in the PICU (median LOS 25 days). Patients spending
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more than 12 days in the PICU are termed as long-stay patients (LSP) who consume
disproportionate amount of health care resources and have higher mortality than short stay
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patients14.
In our cohort lumbar puncture was performed in 60% of the children. One reason for this low number may be that the database only captures procedures done during the hospitalization.
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Therefore, if a lumbar puncture were performed at a referring hospital before transfer, this data would not be available. Lumbar puncture may not be performed for various reasons including, hemodynamic instability, concerns for cerebral edema and risk of herniation, no change in
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management due to not performing the procedure and no clinical indication for lumbar puncture.
40% of children with encephalitis were admitted to the PICU, with median length of stay being 25 days. Children in the PICU had increased use of anti microbials, seizure medications and immunomodulators. Children with encephalitis have a longer length of stay (25 days) compared to the average length of stay for all PICU patients nationally (3.5 days)15. With such increased amount of time in the ICU, not only is the resource utilization higher, but also the chances of
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secondary infections is higher. 23% of our cohort required ventilator support due to respiratory compromise, similar to the 23% reported by Florance et al16.
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Seizures are commonly encountered in children with encephalitis and the use of anti epileptics is frequently based on local experience or expert opinion17. Our data also reflects a wide variation in antiepileptic use with the most frequent being Levetiracetam and Fospheytoin. Also children
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admitted to the PICU are more likely to have seizures when compared to children on the floor (p
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<0.0001) but there was no difference in use of electroencephalogram (EEG).
IDSA and American Neurological Association (ANA) have set out guidelines for the diagnostic and management aspects of encephalitis. There is emphasis to establish the etiologic diagnosis, even though in many cases there is no definitive treatment. Nevertheless identifying an agent or cause will help with prognosis, counseling and public health interventions. Though the workup
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needs to be individualized, our data indicates a wide variation in the diagnostic work up for children with encephalitis. Developing a prospective registry, will help to standardize diagnostic
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evaluation and systematically evaluate management.
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Our data clearly shows an increasing trend with use of IVIG and plasmapheresis in children with encephalitis. We hypothesize that this is due to increased recognition of autoimmune mediated encephalitis including antiNMDAR, anti-Gad etc. In a cohort of 522 patients with anti NMDAR encephalitis 92% received first line immunotherapy including steroids, IVIG, and plasmapheresis alone or combined7. In this study the author’s report 79% of the study population had good outcomes and reported 30 deaths. Predictors of good outcomes were early treatment and no admission to the intensive care unit. In our cohort 144 patients received rituximab. Rituximab, a 11
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human/murine chimeric monocloncal antibody is being administered earlier in the course of immune mediated encephalitis, as it has been associated with improved outcomes18. Because of the retrospective nature and limitation of the database, we are unable to gather information about
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the timing of this therapy. There is lack of consensus on the timing and the sequence of use of first line immunotherapy agents.
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There were 230 hospital deaths (3%), 228 (3%) transferred to inpatient rehabilitation center and
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5944 (81%) children were discharged home. The remaining 13% constituted missing data, transfer to home health services, transferred to other facility and left against medical advice. Mortality for viral encephalitis has been reported ranging from 5% to 100% in rabies19. Britton et al have described mortality to be 10%, with 50% experiencing short term neurological deficits
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and 20% having severe sequelae11.
Our study has limitations related to all retrospective database studies. Certain race groups are more likely to be affected by immune mediated encephalitis, and missing data on race, makes
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analysis difficult. Lack of data on the etiology is a limitation for this study, as that data will be helpful given the wide etiological factors (infectious, immune mediated etc) for encephalitis.
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Another limitation of the study was the inability to determine the lower than expected number of children having a lumbar puncture performed. Details about the laboratory and radiological work up would be helpful to determine the severity of illness and resource utilization according to sub groups of patients. Long term outcomes and prognosis data would be valuable as children being discharged have varying degree of neurological compromise20.
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In conclusion, the burden of resource utilization due to encephalitis in children is significant and children admitted to the PICU are more likely to have longer length of hospitalization and higher mortality. Newer modalities like plasmapheresis and IVIG are being used with increased
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frequency for children admitted with encephalitis. There is variation in the diagnostic work up and use of anti microbials and anti epileptic agents, though the clinical impact on the outcomes cannot be determined. Creation of prospective registries has potential for designing clinical trials
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to determine the optimal therapies especially for the sickest cohorts.
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References:
1. Armangue T, Petit-Pedrol M, Dalmau J. Autoimmune encephalitis in children. J Child Neurol. 2012;27(11):1460-1469. doi: 10.1177/0883073812448838 [doi].
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2. Bitnun A, Richardson SE. Childhood encephalitis in canada in 2015. Can J Infect Dis Med Microbiol. 2015;26(2):69-72.
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3. Glaser CA, Gilliam S, Schnurr D, et al. In search of encephalitis etiologies: Diagnostic challenges in the california encephalitis project, 1998-2000. Clin Infect Dis. 2003;36(6):731-742.
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doi: CID30040 [pii].
4. Elbers JM, Bitnun A, Richardson SE, et al. A 12-year prospective study of childhood herpes simplex encephalitis: Is there a broader spectrum of disease? Pediatrics. 2007;119(2):e399-407. doi: 119/2/e399 [pii].
5. Thompson C, Kneen R, Riordan A, Kelly D, Pollard AJ. Encephalitis in children. Arch Dis Child. 2012;97(2):150-161. doi: 10.1136/archdischild-2011-300100 [doi]. 13
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6. Bloch KC, Glaser CA. Encephalitis surveillance through the emerging infections program, 1997-2010. Emerg Infect Dis. 2015;21(9):1562-1567. doi: 10.3201/eid2109.150295 [doi].
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7. Titulaer MJ, McCracken L, Gabilondo I, et al. Treatment and prognostic factors for long-term outcome in patients with anti-NMDA receptor encephalitis: An observational cohort study. Lancet Neurol. 2013;12(2):157-165. doi: 10.1016/S1474-4422(12)70310-1 [doi].
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8. Falchek SJ. Encephalitis in the pediatric population. Pediatr Rev. 2012;33(3):122-33; quiz 33.
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doi: 10.1542/pir.33-3-122 [doi].
9. Lewis P, Glaser CA. Encephalitis. Pediatr Rev. 2005;26(10):353-363. doi: 26/10/353 [pii].
10. Dalmau J, Gleichman AJ, Hughes EG, et al. Anti-NMDA-receptor encephalitis: Case series and analysis of the effects of antibodies. Lancet Neurol. 2008;7(12):1091-1098. doi:
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10.1016/S1474-4422(08)70224-2 [doi].
11. Britton PN, Eastwood K, Paterson B, et al. Consensus guidelines for the investigation and
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management of encephalitis in adults and children in australia and new zealand. Intern Med J. 2015;45(5):563-576. doi: 10.1111/imj.12749 [doi].
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12. Kittle K, Currier K, Dyk L, Newman K. Using a pediatric database to drive quality improvement. Semin Pediatr Surg. 2002;11(1):60-63. doi: S105585860250010X [pii].
13. Khetsuriani N, Holman RC, Lamonte-Fowlkes AC, Selik RM, Anderson LJ. Trends in encephalitis-associated deaths in the united states. Epidemiol Infect. 2007;135(4):583-591. doi: S0950268806007163 [pii].
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14. Marcin JP, Slonim AD, Pollack MM, Ruttimann UE. Long-stay patients in the pediatric intensive care unit. Crit Care Med. 2001;29(3):652-657.
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15. Levin SR, Harley ET, Fackler JC, et al. Real-time forecasting of pediatric intensive care unit length of stay using computerized provider orders. Crit Care Med. 2012;40(11):3058-3064. doi: 10.1097/CCM.0b013e31825bc399 [doi].
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16. Florance NR, Davis RL, Lam C, et al. Anti-N-methyl-D-aspartate receptor (NMDAR)
[doi].
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encephalitis in children and adolescents. Ann Neurol. 2009;66(1):11-18. doi: 10.1002/ana.21756
17. Fowler A, Stodberg T, Eriksson M, Wickstrom R. Childhood encephalitis in sweden: Etiology, clinical presentation and outcome. Eur J Paediatr Neurol. 2008;12(6):484-490. doi:
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10.1016/j.ejpn.2007.12.009 [doi].
18. Zekeridou A, Karantoni E, Viaccoz A, et al. Treatment and outcome of children and adolescents with N-methyl-D-aspartate receptor encephalitis. J Neurol. 2015. doi:
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10.1007/s00415-015-7781-9 [doi].
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19. Bale JF,Jr. Virus and immune-mediated encephalitides: Epidemiology, diagnosis, treatment, and prevention. Pediatr Neurol. 2015;53(1):3-12. doi: 10.1016/j.pediatrneurol.2015.03.013 [doi].
20. Flett KB, Rao S, Dominguez SR, Bernard T, Glode MP. Variability in the diagnosis of encephalitis by pediatric subspecialists: The need for a uniform definition. J Pediatric Infect Dis Soc. 2013;2(3):267-269. doi: 10.1093/jpids/pis094 [doi].
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Total
Floor
PICU
Hospitalizations
7298
Admissions
n=2933 (40%)
n=4365 (60%) 3758
2182 (58%)
1576 (42%)
9 years
9 years
White
1476 (34%)
1059 (36%)
Black
494 (11%)
362 (12%)
Hispanic
868 (20%)
551 (19%)
Asian
86 (2%)
75 (2%)
American Indian
62 (1%)
12 (<1%)
Other
408 (9%)
299 (10%)
Median Age
stay
1697 (39%)
1157 (39%)
16 days
25 days
p=0.06
230 (3%)
195 (6%)
p=0.01
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Deaths
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Median length of
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Unknown
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Race*
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Males
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All
Table 1: Characteristics of patients hospitalized with encephalitis, all hospitalizations and PICU patients
*Footnote: Data pertaining to race was not reported for over one third of the patients in the cohort
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PICU n=2933
p value
CSF cultures
1860 (42.6%)
1560 (53.1%)
<0.0001
Blood culture
124 (2.84%)
163 (5.55%)
0.02
CMV antigen
27 (0.61%)
36 (1.22%)
0.31
CMV antibody
405 (9.27%)
457 (15.5%)
0.08
CMV culture
71 (1.62%)
73 (2.48%)
0.93
EBV
700 (16%)
674 (22.97%)
0.5
Herpes PCR
2 (<0.05%)
1 (<0.05%)
1
Herpes Antibody
107 (2.45%)
122 (4.15%)
0.35
Herpes Antigen
80 (1.83%)
106 (3.61%)
0.06
Herpes Culture
59 (1.35%)
56 (1.93%)
0.85
HHV 6 antibody
7 (0.16%)
10 (0.34%)
0.62
West Nile Virus antibody blood
189 (4.32%)
205 (6.98%)
0.44
West Nile Virus antibody CSF
21 (0.48%)
33 (1.1%)
0.13
WesternEquineEncephalitisAntibody
122 (2.79%)
179 (6.1%)
0.0012
StLouisEquineEncephalitisAntibody
120 (2.74%)
174 (5.93%)
0.002
VaricellaZosterSerologyBlood
114 (2.61%)
159 (5.42%)
0.007
HIV1Antibody
119 (2.72%)
147(5.01%)
0.09
HIV2Antibody
20 (0.45%)
24 (0.81%)
0.65
HIV antigen
2 (<0.05%)
8 (0.27%)
0.11
HIV Westernblot
4 (0.09%)
5 (0.17%)
1
HIV DNA PCR
30 (0.68%)
48 (1.63%)
0.05
CryptococcusAntigen
20 (0.45%)
30 (1.02%)
0.2
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Floor n=4365
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Investigations
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3 (0.06%)
7 (0.23%)
0.34
Fungal Culture Blood
93 (2.1%)
181 (6.17%)
<0.0001
Fungal Culture CSF
6 (0.13%)
9 (0.3%)
0.6
RickettsialAntibodyBlood
24 (0.54%)
57 (1.94%)
0.0004
Mycobacterial culture
163 (3.73%)
377 (12.83%)
<0.0001
Acid Fast Stain
160 (3.66%)
333 (11.35%)
<0.0001
QuantiFERONTBGold
37 (0.84%)
63 (2.14%)
0.01
Mycoplasma serology
520 (11.91%)
559 (19.05%)
0.24
Mycoplasma DNA probe
237 (5.42%)
304 (10.36%)
0.004
Lyme Disease Blood
320 (7.33%)
202 (6.88%)
<0.0001
Lyme Disease CSF
26 (0.59%)
18 (0.61%)
0.29
205 (4.69%)
234 (7.97%)
0.18
412 (9.43%)
274 (9.34%)
<0.0001
259 (5.93%)
250 (5.52%)
0.72
2521 (57.75%)
1860 (63.41%)
Lumbar puncture
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EEG
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Head MRI
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Head CT
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CryptococcusAntibody
Table 2: Laboratory investigations and diagnostic procedures for children admitted with encephalitis
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Anti microbial
PICU
n=4365
n=2933
Fosphenytoin
407 (9%)
1178 (40%)
<0.0001
Phenobarbital
234(5%)
588 (20%)
<0.0001
Lamictal
71 (2%)
39 (1%)
0.0012
Levetiracetam
586 (13%)
1027 (35%)
<0.0001
Pentobarbital
446 (10%)
517 (17%)
<0.0001
Vancomycin
763 (17%)
1743 (59%)
<0.0001
Ceftriaxone
1024 (23%)
1461 (50%)
<0.0001
398(9%)
687 (23%)
<0.0001
1194 (27%)
1618 (55%)
<0.0001
1714 (39%)
1286 (44%)
<0.0001
63 (1%)
65 (2%)
0.0005
Rituximab
60 (1%)
84 (2%)
0.0005
Cyclophosphamide
142 (3%)
155 (5%)
<0.0001
IVIG
538 (12%)
675 (23%)
<0.0001
Cefotaxime Acyclovir Immunomodulator
Methylprednisone
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Methotrexate
p value
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Anti epileptics
Floor
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Drug
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Class
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Table 3: Utilization of medications for patients hospitalized with encephalitis
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Plasmapheresis 14
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12 10 8
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6 4
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2 0
2004 2005 2006 2007 2008 2009 2010 2011 2012 2013
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Figure 1: Proportion of Hospitalized Children with Encephalitis undergoing Plasmapheresis over a 10 year period
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25
IVIG
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20 15
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10
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5 0 2004
2005 2006 2007 2008 2009 2010 2011 2012 2013
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Figure 2: Proportion of Hospitalized Children with Encephalitis receiving IVIG over a 10 year period
S0887-8994(16)30074-1
DOI:
10.1016/j.pediatrneurol.2016.04.014
Reference:
PNU 8902
To appear in:
Pediatric Neurology
Received Date: 10 February 2016 Revised Date:
29 April 2016
Accepted Date: 30 April 2016
Please cite this article as: Bagdure D, Custer JW, Rao S, Messacar K, Dominguez S, Beam BW, Bhutta A, Hospitalized Children with Encephalitis in United States: A PHIS Database Study, Pediatric Neurology (2016), doi: 10.1016/j.pediatrneurol.2016.04.014. 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.
ACCEPTED MANUSCRIPT
Hospitalized Children with Encephalitis in United States: A PHIS Database
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Study
Dayanand Bagdure MBBS MPH1, Jason W Custer. MD1, Suchitra Rao MD2, Kevin Messacar,
1
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MD2, Samuel Dominguez, MD PhD2, Brandon W Beam, JD3, Adnan Bhutta, MBBS1. Department of Pediatrics; Division of Pediatric Critical Care Medicine, University of Maryland
2
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School of Medicine, Baltimore, MD
Department of Pediatrics; Division of Infectious Diseases, University of Colorado School of
Medicine, Aurora, CO
Informatics, Arkansas Children’s Hospital, Little Rock, AR
Corresponding Author:
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Dayanand Bagdure MBBS MPH
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110 S Paca St 8th Floor Baltimore MD 21202
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Phone No: 410-328-6957
Cell Phone No: 786-543-0577 Fax No: 410-328-0680
Email: [email protected]
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Keywords: encephalitis, children, pediatric critical care, plasmapheresis Disclosure: Dr.Bagdure received funding from The PATIENTS program which is funded
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HS22135-01]. Other authors do not have any financial disclosures.
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through Agency for Healthcare and Research and Quality (AHRQ) [Grant Number: R24
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Abstract: Objectives: Given the paucity of data on resource utilization among children with encephalitis,
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the objective of the study is to describe the epidemiology, evaluate resource utilization, and discharge data of children with encephalitis admitted to United States hospitals from 2004-2013. Methods: We conducted a retrospective cohort study utilizing the Pediatric Health Information
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System (PHIS) database of children aged 0-18 years with ICD-9 codes for encephalitis from 2004-2013. Only the initial admissions were included and the age group analyzed was 0-18 years
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of age.
Results: Among 7298 children with encephalitis, 2933 (40%) were admitted to the PICU. The median age was 9 years and the overall median length of stay was 16 days, and children
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requiring critical care had median length of stay of 25 days. Children in the PICU were more likely to have seizures (<0.001) and head MRI imaging (<0.001) as compared to children on the floor. Similarly, children requiring critical care were more likely to have a broad diagnostic
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workup sent including CSF cultures, blood bacterial and fungal cultures, western equine encephalitis antibody, St. Louis Equine encephalitis antibody, varicella zoster serology, HIV 1
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antibody, HIV DNA PCR, Acid Fast stain, and lyme disease serology. 17% of children were treated with intravenous immunoglobulin (IVIG) and 4% underwent plasmapheresis. There was a trend of increasing use of IVIG and plasmapheresis in children with encephalitis over the studied period. 5944 (81%) of the children were discharged home and the mortality in this cohort was 3% (230). The mean charges for hospitalization for a child with encephalitis was $64604, and for those requiring critical care was $260012.
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Conclusions: Encephalitis is a significant cause of morbidity and mortality in children. Children with encephalitis admitted to the PICU are more likely have seizures, more extensive work up to determine the cause of encephalitis. Use of plasmapheresis and intravenous immunoglobulin
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(IVIG) is on a rise in hospitalized children. Prospective studies are necessary to better understand
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treatment and intervention strategies for children with encephalitis and their impact on outcomes.
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Introduction:
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Data regarding the health care burden of encephalitis in children remains unknown. The etiologies of encephalitis in children range from infectious (including bacterial, viral, fungal and parasitic diseases) to autoimmune processes1,2. Diagnosing the cause of encephalitis is often an
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exhaustive and expensive endeavor and even then 60% of the cases remain undiagnosed3.
Because of the varied etiologies, outcomes of encephalitis range from acute illness with rapid
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reversibility of symptoms to chronic debilitating conditions. Mortality though low, can be seen in infectious causes like herpes simplex encephalitis4.
Historically bacterial and viral encephalitis is discussed widely in literature with recent emphasis on antibody mediated encephalitis5. Even with comprehensive diagnostic evaluations using
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advanced diagnostic techniques, over 60% of cases of encephalitis remain without a clear etiology (California encephalitis study)6. In order to drive research into understanding the epidemiology and improving therapeutics for encephalitis, it is imperative to determine the
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hospital burden of encephalitis and the use of current therapies employed in children.
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Infectious Disease Society of America (IDSA) defines encephalitis as presence of an inflammatory process of the brain in association of clinical evidence of neurologic dysfunction 7. Encephalitis is either due to direct invasion of the central nervous system (CNS) or indirect involvement of the CNS8. Encephalitis is a histopathologic diagnosis, however brain biopsies are rarely performed due to their invasive nature. Consensus clinical diagnostic criteria have been published which evaluate clinical factors that suggest parenchymal inflammation, such as
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neuroimaging changes, electroencephalography changes, focal neurologic deficits and seizures9. In order to determine the causative agent cerebrospinal fluid analysis is performed in most cases. In addition, sampling of respiratory secretions, stool, and blood is conducted to look for
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pathogens associated with encephalitis at other sites. It is difficult to determine the significance of an infectious agent found outside of the CNS as the cause of encephalitis and often these are
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considered probable or possible causes.
As we continue to better recognize and understand immune mediated encephalitis (including
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anti-NMDA and other anti-neuronal antibodies), procedures like plasmapheresis and medications like intravenous immune globulin (IVIG) and immunomodulators are being utilized more frequently and earlier in the disease process10,11.
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Querying large administrative databases offer an opportunity to understand disease burden, report on trends of hospitalization and resource utilization, and evaluate outcomes. It also helps
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to understand the variation in management of diseases or disorders across numerous hospitals.
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Patients and Methods:
Data source
We retrospectively reviewed cases of encephalitis using the Pediatric Health Information System (PHIS)12. PHIS is a comprehensive pediatric database containing administrative and financial details for more than six million hospitalizations from 44 participating free standing children’s
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hospitals. The PHIS database includes patient demographic information, diagnoses and procedures data coded with International Classification of Diseases, 9th Revision (ICD-9) codes, resource utilization data, and outcome data. Data is extracted using ICD-9 codes, obviating the
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need for definitions for diagnoses. Data regarding laboratory investigations, medications,
imaging studies and other resource utilization data is coded under the Clinical Transaction
Classification (CTC) system (Truven Health Analytics, Ann Arbor, MI). Procedures are coded
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using both ICD-9 and CTC codes.
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The University of Maryland Institutional Review Board for the Protection of Human Subjects reviewed the study protocol and determined that this study does not fall under the jurisdiction of the Institutional Review Board review process.
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Study Population:
The study population was defined as all patients in the age group less than 18 years admitted to a
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PHIS participating hospital from 2004 – 2013 with a primary or secondary discharge diagnosis of encephalitis (ICD-9, 323, 323.01, 323.02, 323.1, 323.2, 323.4, 323.41, 323.42, 323.5, 323.51,
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323.52, 323.6, 323.61, 323.62, 323.63, 323.7, 323.71, 323.72, 323.8, 323.81, 323.82,323.9)13. Analysis was limited to first hospitalization only.
Data Collection:
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Data collection included demographic information, year of admission, source of admission, race and ethnicity, admission age and length of stay. We queried the data base for medication utilization including antibiotic and antiepileptic medications, imaging studies including imaging
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with CT, MRI; procedures including lumbar puncture, dialysis, mechanical ventilation and
plasmapheresis. Hospitalization charges for hospital stay and ICU stay were obtained. Outcomes
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data included mortality and disposition type (home, rehabilitation center).
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Statistical Analysis:
Descriptive statistics were calculated in Microsoft Excel 2007. Data are described with median and inter quartile range. Group differences were compared using chi-square tests for categorical variables and Mann-Whitney tests for continuously distributed variables. Statistical significance
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was defined as a p value < 0.05.
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Results
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Demographic data:
There were 7298 admissions for encephalitis during the years 2004-2013, of which 2933 (40%) were admitted to the intensive care unit. From 2004 to 2013 number of children with encephalitis increased from 593 to 847. The demographics of these patients are shown in Table 1. The median age at time of diagnosis was 9 years (IQR 3.8-13.3). Data on race was difficult to interpret as for over a third of the patient’s data on race was not reported. There were 230 deaths,
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and median length of hospital stay was 16 days (IQR 5-441). Of the cohort, 40% (2933) of the children were admitted to the PICU. Median length of stay in the PICU was 25 days.
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Procedures and Investigations:
4381 (60%) of children underwent lumbar puncture, 427 (14.5%) had an arterial line placed,
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1698 (58%) had a central line placed and 145 (5%) had tracheostomy in children admitted to the PICU. There were 41 (0.56%) children with encephalitis who received cardiopulmonary
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resuscitation during their hospital stay and 6 (<0.5%) children had pacemaker placed. 62 (2%) children had intracranial pressure monitoring device. Children admitted to the PICU (27%) were more likely to have seizures when compared to children admitted to the floor (12%) (p<0.0001).
Treatment data:
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Table 2 lists the investigations for these patients obtained from the database.
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Table 3 details the use of anti epileptics, anti-microbials and immunomodulators in this cohort. Over the 10 year period 2003-2014 there was increase in the number of patients receiving
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plasmapheresis and IVIG. Figure 1 shows the proportion of children admitted for encephalitis undergoing plasmapheresis. Figure 2 shows the proportion of children who received IVIG. Mean charges of hospitalization for a child with encephalitis on the floor was $64604 and in the PICU it was $260012. Table 2 shows the laboratory investigations and diagnostic procedures done on the cohort.
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Discussion:
We report the largest epidemiological study of inpatient children with encephalitis in the United
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States. Over a 10 year period there were increasing number of children being admitted with encephalitis and there was increase in the use of plasmapheresis and IVIG. Children with
encephalitis spend significant longer time in the PICU (median LOS 25 days). Patients spending
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more than 12 days in the PICU are termed as long-stay patients (LSP) who consume
disproportionate amount of health care resources and have higher mortality than short stay
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patients14.
In our cohort lumbar puncture was performed in 60% of the children. One reason for this low number may be that the database only captures procedures done during the hospitalization.
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Therefore, if a lumbar puncture were performed at a referring hospital before transfer, this data would not be available. Lumbar puncture may not be performed for various reasons including, hemodynamic instability, concerns for cerebral edema and risk of herniation, no change in
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management due to not performing the procedure and no clinical indication for lumbar puncture.
40% of children with encephalitis were admitted to the PICU, with median length of stay being 25 days. Children in the PICU had increased use of anti microbials, seizure medications and immunomodulators. Children with encephalitis have a longer length of stay (25 days) compared to the average length of stay for all PICU patients nationally (3.5 days)15. With such increased amount of time in the ICU, not only is the resource utilization higher, but also the chances of
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secondary infections is higher. 23% of our cohort required ventilator support due to respiratory compromise, similar to the 23% reported by Florance et al16.
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Seizures are commonly encountered in children with encephalitis and the use of anti epileptics is frequently based on local experience or expert opinion17. Our data also reflects a wide variation in antiepileptic use with the most frequent being Levetiracetam and Fospheytoin. Also children
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admitted to the PICU are more likely to have seizures when compared to children on the floor (p
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<0.0001) but there was no difference in use of electroencephalogram (EEG).
IDSA and American Neurological Association (ANA) have set out guidelines for the diagnostic and management aspects of encephalitis. There is emphasis to establish the etiologic diagnosis, even though in many cases there is no definitive treatment. Nevertheless identifying an agent or cause will help with prognosis, counseling and public health interventions. Though the workup
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needs to be individualized, our data indicates a wide variation in the diagnostic work up for children with encephalitis. Developing a prospective registry, will help to standardize diagnostic
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evaluation and systematically evaluate management.
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Our data clearly shows an increasing trend with use of IVIG and plasmapheresis in children with encephalitis. We hypothesize that this is due to increased recognition of autoimmune mediated encephalitis including antiNMDAR, anti-Gad etc. In a cohort of 522 patients with anti NMDAR encephalitis 92% received first line immunotherapy including steroids, IVIG, and plasmapheresis alone or combined7. In this study the author’s report 79% of the study population had good outcomes and reported 30 deaths. Predictors of good outcomes were early treatment and no admission to the intensive care unit. In our cohort 144 patients received rituximab. Rituximab, a 11
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human/murine chimeric monocloncal antibody is being administered earlier in the course of immune mediated encephalitis, as it has been associated with improved outcomes18. Because of the retrospective nature and limitation of the database, we are unable to gather information about
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the timing of this therapy. There is lack of consensus on the timing and the sequence of use of first line immunotherapy agents.
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There were 230 hospital deaths (3%), 228 (3%) transferred to inpatient rehabilitation center and
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5944 (81%) children were discharged home. The remaining 13% constituted missing data, transfer to home health services, transferred to other facility and left against medical advice. Mortality for viral encephalitis has been reported ranging from 5% to 100% in rabies19. Britton et al have described mortality to be 10%, with 50% experiencing short term neurological deficits
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and 20% having severe sequelae11.
Our study has limitations related to all retrospective database studies. Certain race groups are more likely to be affected by immune mediated encephalitis, and missing data on race, makes
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analysis difficult. Lack of data on the etiology is a limitation for this study, as that data will be helpful given the wide etiological factors (infectious, immune mediated etc) for encephalitis.
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Another limitation of the study was the inability to determine the lower than expected number of children having a lumbar puncture performed. Details about the laboratory and radiological work up would be helpful to determine the severity of illness and resource utilization according to sub groups of patients. Long term outcomes and prognosis data would be valuable as children being discharged have varying degree of neurological compromise20.
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In conclusion, the burden of resource utilization due to encephalitis in children is significant and children admitted to the PICU are more likely to have longer length of hospitalization and higher mortality. Newer modalities like plasmapheresis and IVIG are being used with increased
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frequency for children admitted with encephalitis. There is variation in the diagnostic work up and use of anti microbials and anti epileptic agents, though the clinical impact on the outcomes cannot be determined. Creation of prospective registries has potential for designing clinical trials
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to determine the optimal therapies especially for the sickest cohorts.
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References:
1. Armangue T, Petit-Pedrol M, Dalmau J. Autoimmune encephalitis in children. J Child Neurol. 2012;27(11):1460-1469. doi: 10.1177/0883073812448838 [doi].
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2. Bitnun A, Richardson SE. Childhood encephalitis in canada in 2015. Can J Infect Dis Med Microbiol. 2015;26(2):69-72.
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3. Glaser CA, Gilliam S, Schnurr D, et al. In search of encephalitis etiologies: Diagnostic challenges in the california encephalitis project, 1998-2000. Clin Infect Dis. 2003;36(6):731-742.
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doi: CID30040 [pii].
4. Elbers JM, Bitnun A, Richardson SE, et al. A 12-year prospective study of childhood herpes simplex encephalitis: Is there a broader spectrum of disease? Pediatrics. 2007;119(2):e399-407. doi: 119/2/e399 [pii].
5. Thompson C, Kneen R, Riordan A, Kelly D, Pollard AJ. Encephalitis in children. Arch Dis Child. 2012;97(2):150-161. doi: 10.1136/archdischild-2011-300100 [doi]. 13
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6. Bloch KC, Glaser CA. Encephalitis surveillance through the emerging infections program, 1997-2010. Emerg Infect Dis. 2015;21(9):1562-1567. doi: 10.3201/eid2109.150295 [doi].
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7. Titulaer MJ, McCracken L, Gabilondo I, et al. Treatment and prognostic factors for long-term outcome in patients with anti-NMDA receptor encephalitis: An observational cohort study. Lancet Neurol. 2013;12(2):157-165. doi: 10.1016/S1474-4422(12)70310-1 [doi].
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8. Falchek SJ. Encephalitis in the pediatric population. Pediatr Rev. 2012;33(3):122-33; quiz 33.
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doi: 10.1542/pir.33-3-122 [doi].
9. Lewis P, Glaser CA. Encephalitis. Pediatr Rev. 2005;26(10):353-363. doi: 26/10/353 [pii].
10. Dalmau J, Gleichman AJ, Hughes EG, et al. Anti-NMDA-receptor encephalitis: Case series and analysis of the effects of antibodies. Lancet Neurol. 2008;7(12):1091-1098. doi:
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10.1016/S1474-4422(08)70224-2 [doi].
11. Britton PN, Eastwood K, Paterson B, et al. Consensus guidelines for the investigation and
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management of encephalitis in adults and children in australia and new zealand. Intern Med J. 2015;45(5):563-576. doi: 10.1111/imj.12749 [doi].
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12. Kittle K, Currier K, Dyk L, Newman K. Using a pediatric database to drive quality improvement. Semin Pediatr Surg. 2002;11(1):60-63. doi: S105585860250010X [pii].
13. Khetsuriani N, Holman RC, Lamonte-Fowlkes AC, Selik RM, Anderson LJ. Trends in encephalitis-associated deaths in the united states. Epidemiol Infect. 2007;135(4):583-591. doi: S0950268806007163 [pii].
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14. Marcin JP, Slonim AD, Pollack MM, Ruttimann UE. Long-stay patients in the pediatric intensive care unit. Crit Care Med. 2001;29(3):652-657.
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15. Levin SR, Harley ET, Fackler JC, et al. Real-time forecasting of pediatric intensive care unit length of stay using computerized provider orders. Crit Care Med. 2012;40(11):3058-3064. doi: 10.1097/CCM.0b013e31825bc399 [doi].
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16. Florance NR, Davis RL, Lam C, et al. Anti-N-methyl-D-aspartate receptor (NMDAR)
[doi].
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encephalitis in children and adolescents. Ann Neurol. 2009;66(1):11-18. doi: 10.1002/ana.21756
17. Fowler A, Stodberg T, Eriksson M, Wickstrom R. Childhood encephalitis in sweden: Etiology, clinical presentation and outcome. Eur J Paediatr Neurol. 2008;12(6):484-490. doi:
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10.1016/j.ejpn.2007.12.009 [doi].
18. Zekeridou A, Karantoni E, Viaccoz A, et al. Treatment and outcome of children and adolescents with N-methyl-D-aspartate receptor encephalitis. J Neurol. 2015. doi:
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10.1007/s00415-015-7781-9 [doi].
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19. Bale JF,Jr. Virus and immune-mediated encephalitides: Epidemiology, diagnosis, treatment, and prevention. Pediatr Neurol. 2015;53(1):3-12. doi: 10.1016/j.pediatrneurol.2015.03.013 [doi].
20. Flett KB, Rao S, Dominguez SR, Bernard T, Glode MP. Variability in the diagnosis of encephalitis by pediatric subspecialists: The need for a uniform definition. J Pediatric Infect Dis Soc. 2013;2(3):267-269. doi: 10.1093/jpids/pis094 [doi].
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Total
Floor
PICU
Hospitalizations
7298
Admissions
n=2933 (40%)
n=4365 (60%) 3758
2182 (58%)
1576 (42%)
9 years
9 years
White
1476 (34%)
1059 (36%)
Black
494 (11%)
362 (12%)
Hispanic
868 (20%)
551 (19%)
Asian
86 (2%)
75 (2%)
American Indian
62 (1%)
12 (<1%)
Other
408 (9%)
299 (10%)
Median Age
stay
1697 (39%)
1157 (39%)
16 days
25 days
p=0.06
230 (3%)
195 (6%)
p=0.01
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Deaths
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Median length of
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Unknown
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Race*
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Males
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All
Table 1: Characteristics of patients hospitalized with encephalitis, all hospitalizations and PICU patients
*Footnote: Data pertaining to race was not reported for over one third of the patients in the cohort
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p value
CSF cultures
1860 (42.6%)
1560 (53.1%)
<0.0001
Blood culture
124 (2.84%)
163 (5.55%)
0.02
CMV antigen
27 (0.61%)
36 (1.22%)
0.31
CMV antibody
405 (9.27%)
457 (15.5%)
0.08
CMV culture
71 (1.62%)
73 (2.48%)
0.93
EBV
700 (16%)
674 (22.97%)
0.5
Herpes PCR
2 (<0.05%)
1 (<0.05%)
1
Herpes Antibody
107 (2.45%)
122 (4.15%)
0.35
Herpes Antigen
80 (1.83%)
106 (3.61%)
0.06
Herpes Culture
59 (1.35%)
56 (1.93%)
0.85
HHV 6 antibody
7 (0.16%)
10 (0.34%)
0.62
West Nile Virus antibody blood
189 (4.32%)
205 (6.98%)
0.44
West Nile Virus antibody CSF
21 (0.48%)
33 (1.1%)
0.13
WesternEquineEncephalitisAntibody
122 (2.79%)
179 (6.1%)
0.0012
StLouisEquineEncephalitisAntibody
120 (2.74%)
174 (5.93%)
0.002
VaricellaZosterSerologyBlood
114 (2.61%)
159 (5.42%)
0.007
HIV1Antibody
119 (2.72%)
147(5.01%)
0.09
HIV2Antibody
20 (0.45%)
24 (0.81%)
0.65
HIV antigen
2 (<0.05%)
8 (0.27%)
0.11
HIV Westernblot
4 (0.09%)
5 (0.17%)
1
HIV DNA PCR
30 (0.68%)
48 (1.63%)
0.05
CryptococcusAntigen
20 (0.45%)
30 (1.02%)
0.2
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Floor n=4365
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Investigations
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3 (0.06%)
7 (0.23%)
0.34
Fungal Culture Blood
93 (2.1%)
181 (6.17%)
<0.0001
Fungal Culture CSF
6 (0.13%)
9 (0.3%)
0.6
RickettsialAntibodyBlood
24 (0.54%)
57 (1.94%)
0.0004
Mycobacterial culture
163 (3.73%)
377 (12.83%)
<0.0001
Acid Fast Stain
160 (3.66%)
333 (11.35%)
<0.0001
QuantiFERONTBGold
37 (0.84%)
63 (2.14%)
0.01
Mycoplasma serology
520 (11.91%)
559 (19.05%)
0.24
Mycoplasma DNA probe
237 (5.42%)
304 (10.36%)
0.004
Lyme Disease Blood
320 (7.33%)
202 (6.88%)
<0.0001
Lyme Disease CSF
26 (0.59%)
18 (0.61%)
0.29
205 (4.69%)
234 (7.97%)
0.18
412 (9.43%)
274 (9.34%)
<0.0001
259 (5.93%)
250 (5.52%)
0.72
2521 (57.75%)
1860 (63.41%)
Lumbar puncture
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EEG
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Head MRI
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Head CT
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CryptococcusAntibody
Table 2: Laboratory investigations and diagnostic procedures for children admitted with encephalitis
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Anti microbial
PICU
n=4365
n=2933
Fosphenytoin
407 (9%)
1178 (40%)
<0.0001
Phenobarbital
234(5%)
588 (20%)
<0.0001
Lamictal
71 (2%)
39 (1%)
0.0012
Levetiracetam
586 (13%)
1027 (35%)
<0.0001
Pentobarbital
446 (10%)
517 (17%)
<0.0001
Vancomycin
763 (17%)
1743 (59%)
<0.0001
Ceftriaxone
1024 (23%)
1461 (50%)
<0.0001
398(9%)
687 (23%)
<0.0001
1194 (27%)
1618 (55%)
<0.0001
1714 (39%)
1286 (44%)
<0.0001
63 (1%)
65 (2%)
0.0005
Rituximab
60 (1%)
84 (2%)
0.0005
Cyclophosphamide
142 (3%)
155 (5%)
<0.0001
IVIG
538 (12%)
675 (23%)
<0.0001
Cefotaxime Acyclovir Immunomodulator
Methylprednisone
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Methotrexate
p value
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Anti epileptics
Floor
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Drug
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Class
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Table 3: Utilization of medications for patients hospitalized with encephalitis
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Plasmapheresis 14
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12 10 8
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6 4
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2 0
2004 2005 2006 2007 2008 2009 2010 2011 2012 2013
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Figure 1: Proportion of Hospitalized Children with Encephalitis undergoing Plasmapheresis over a 10 year period
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25
IVIG
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20 15
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10
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5 0 2004
2005 2006 2007 2008 2009 2010 2011 2012 2013
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Figure 2: Proportion of Hospitalized Children with Encephalitis receiving IVIG over a 10 year period