Title: Cost of Managing Meningitis and Encephalitis among Adult Patients in the United States

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1 Accepted Manuscript Title: Cost of Managing Meningitis and Encephalitis among Adult Patients in the United States Authors: J.M. Balada-Llasat, Ning Rosenthal, Rodrigo Hasbun, Louise Zimmer, Christine C. Ginocchio, Steven Duff, Jessica Chung, Samuel Bozzette PII: S (18)30883-X DOI: Reference: IJID 3222 To appear in: International Journal of Infectious Diseases Received date: Revised date: Accepted date: Please cite this article as: Balada-Llasat JM, Rosenthal Ning, Hasbun Rodrigo, Zimmer Louise, Ginocchio Christine C, Duff Steven, Chung Jessica, Bozzette Samuel.Cost of Managing Meningitis and Encephalitis among Adult Patients in the United States.International Journal of Infectious Diseases 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.

2 Cost of Managing Meningitis and Encephalitis among Adult Patients in the United States JM Balada-Llasat*, PharmD, PhD 1*, Ning Rosenthal, MD, MPH, PhD 2, Rodrigo Hasbun MD, MPH 3, Louise Zimmer, MA 4, Christine C. Ginocchio, PhD 4, 5, 6, Steven Duff, MS 7, Jessica Chung PhD, MPH 2, Samuel Bozzette, MD, PhD 2, 8 1 Department of Pathology, The Ohio State University Wexner Medical Center; OH 2 Premier Research Services, Premier Healthcare Solutions Inc, Charlotte, NC 3 University of Texas Health Science Center; Houston, TX 4 biomérieux; Durham, NC 5 BioFire Diagnostics, LLC, Salt lake City, UT Hofstra North Shore-LIJ School of Medicine, Hempstead, NY 7 Veritas Health Economics Consulting; Carlsbad, CA 8 University of California, San Diego, CA Running Title: Meningitis and Encephalitis Management Cost in the US *Corresponding Author: Joan-Miquel Balada-Llasat, PharmD. Ph.D. D (ABMM) 1

3 Director, Immunology Associate Director, Clinical Microbiology Associate Professor, Clinical Pathology 181 Taylor Avenue, Columbus, Ohio Office Abstract Objectives To determine the associated cost related to diagnosis and treatment of meningoencephalitis (ME) in adult patients in the United States. Methods A retrospective observational study design was used to assess the use and costs of diagnostic tests, antimicrobial treatment and total hospitalization for adult patients with suspected ME who received a lumbar puncture (LP) procedure during an emergency department visit or during the first two service days of an inpatient stay. Related costs were calculated by timing of LP performed and infectious etiology. Results Of the 26,429 adult patients with suspected ME diagnosed between included in the study, the mean hospitalization cost was $15,572 ± 27,168 with antimicrobial medication cost and laboratory test costs of $1,144 ± 4,052 and $210 ± 2

4 244, respectively. Total visit cost increased with delayed LP procedure, ICU stay and if the etiology was fungi, arbovirus, or bacteria. Conclusions Higher diagnostic and treatment costs are associated with delayed LP procedure, etiologic agent and if ICU stay is required. Keywords: meningitis, encephalitis, cost, diagnosis, adults INTRODUCTION Meningitis is a syndrome that refers to the inflammation of the meninges, the membranes surrounding the brain and spinal cord. Meningitis manifests with headache and nuchal rigidity and it is usually diagnosed by the examination of the cerebrospinal fluid (CSF) (Richie and Josephson, 2015). In contrast, encephalitis is the inflammation of the brain parenchyma and frequently manifests in focal neurologic deficits or seizures (Richie and Josephson, 2015). Meningitis and encephalitis (ME) are often caused by infectious pathogens including bacteria, viruses, fungi and parasites. However non-infectious conditions such as certain autoimmune diseases and cancer may play a role in some cases (Richie and Josephson, 2015). Common pathogens include Streptococcus pneumoniae, Neisseria meningitidis, Haemophilus influenzae, Listeria monocytogenes, Escherichia coli, Mycobacterium tuberculosis, enteroviruses (EV), varicella zoster virus (VZV), human immunodeficiency virus (HIV), herpes simplex (HSV) types 1, and 2, human herpes virus type 6 (HHV6), mosquito-transmitted encephalitis viruses (e.g., West Nile Virus), Cryptococcus neoformans, and cysticercosis (Romero and Newland, 2003, Thigpen et al., 2011). Depending on the ME etiology, 3

5 there is clinical overlap due to the broad differential diagnoses. If untreated, there is a high risk of morbidity and mortality especially with bacterial and HSV infections (Richie and Josephson, 2015). Although early diagnosis and appropriate treatment are vital to prevent severe and irreversible neurological damages with some of the etiologic agents including death, the diverse causes and frequently atypical symptoms of ME have posed significant challenges for making a correct and timely diagnosis (Richie and Josephson, 2015). Usually patients are rapidly triaged and empiric therapy started. Then, based on risk factors and clinical characteristics, etiologic-specific testing is performed (Richie and Josephson, 2015). Delayed diagnosis may lead to inappropriate treatment, more severe complications and prolonged hospital stays (Hasbun et al., 2013, Khoury et al., 2012). Conventional testing may take up to 72 hours, may be insensitive for certain pathogens, and may be frequently negative due to empiric antibiotic treatment. Additionally, the detection of viral pathogens require molecular diagnostic methods, which may not be available at the clinical site, thereby requiring referral to a reference laboratory with a delayed diagnosis of up to 7 days. A retrospective observational study design was used to assess utilization and related costs of diagnostic tests, antimicrobial treatment and total hospitalization costs for adult patients with suspected ME since the data is lacking. Related costs were calculated by timing of LP performed and all pathogen types. 4

6 METHODS Data source The study population was selected from the largest hospital administrative database in the U.S., Premier Health Database (PHD), which covers about one in five hospital discharges in the nation since Previous analysis showed that the patient and hospital characteristics of the database were comparable to the national inpatient sample characteristics. Data contains more than 590 million patient encounters with complete census of inpatients and hospital-based outpatients from geographically diverse hospitals in the United States. Patients can be tracked across the inpatient and hospital-based outpatient settings, as well as across visits with a unique identifier. A subset of hospitals contributed laboratory data on all microbiologyrelated specimens related to potential infections. Each specimen result includes all observations for that specimen. The microbiology testing results were used to assess specific test findings for different pathogens. All data was de-identified in accordance with HIPAA. Study population The study population included adult patients ( 18 years) who received a LP procedure during an emergency department (ED) visit or during the first two service days of an inpatient stay between Outpatient is defined as patients treated in outpatient settings and were not admitted to the hospital and inpatient as patients admitted for inpatient care. The LP procedure was identified through the International Classification of Diseases (ICD) 9 code of or having a Current Procedural Terminology (CPT) code of ICD-9 codes were used to identify 5

7 patients with an admission or discharge (including both primary and secondary) diagnosis of ME and disease etiology. Patients with ME due to bacteria, herpes viruses, arbovirus, EV, other viruses, fungus, or unknown pathogens were included in the study. For patients with cryptococcal meningitis who received multiple LPs during the same hospitalization, only the first LP procedure was included in the LP-related cost estimate; if patients did not have cryptococcal meningitis, all LP procedures administered during the index admission was included in the LP-related cost estimate. Patients were excluded if they were admitted with any type of trauma or they had chronic meningitis (ICD-9 diagnosis code: 322.2) or CSF shunt, craniotomies, spinal procedures, or head trauma with CSF leaks during the 30 days prior to admission and at time of admission. Outcomes The primary outcomes included treatment and diagnosis-related costs and outcomes by pathogen type. We also assessed the total number of the most commonly performed tests from CSF specimens. These were determined by capturing the comparable tests orders, however due to major differences in coding of the tests not all were able to be included. The following CSF tests were assessed: Gram stain, India Ink stain, glucose, protein, cell count and differential, culture (bacterial, acid fast bacteria [AFB), viral, fungal), PCR (HSV, EV, Lyme disease, West Nile Virus [WNV), Mycobacterium tuberculosis, Epstein Barr virus [EBV), HHV-6, cytomegalovirus [CMV]), Cryptococcal antigen test, bacterial antigen tests. Additionally other antigen tests (urinary antigen), serum antibody tests (WNV, Lyme 6

8 disease, Coccidioides spp., HSV, Cryptococcus spp., CMV, VZV), and serum lactic acid were evaluated. Statistical Methods Patient-, hospital-, and visit-level characteristics were summarized using frequencies and percentages for categorical variables and using mean and standard deviation for each subgroup. All cost calculations were adjusted to 2015 U.S. dollars based on Consumer Price Index for all urban consumers for hospital and related services. Costs were reported by timing of LP procedure and pathogen type. All analyses were performed using SAS (v9.4) (SAS Institute Inc. Cary, NC, USA). 7

9 RESULTS A total of 26,429 adult patients were included in the study sample. Slightly over half (53.3%) were female (Table 1). About 45.9% had public insurance and 40.1% had private insurance; only 12.5% were uninsured. Overall, 91.2% were inpatients. A higher percentage of inpatients were male than outpatients (data not shown). Inpatients and outpatients did not differ significantly in race/ethnicity. CSF Gram stain, glucose, protein and cell count/differential were recorded for 87.8%, 63.8%, 63.6%, 49.4% of patients, respectively (Table 2). CSF AFB and fungal cultures, and antibody tests were conducted for 13 17% of patients. Overall, PCR tests were only conducted for 8.9% of the patients. Cryptococcal antigen test, other antigen tests and India Ink stains were only used for 7%, 1.1% and 3% of patients, respectively (Table 2). Among patients with microbiology data available, 14,965 had bacterial culture and of these 8.0% were positive; 1,033 had viral culture of which 10.9% were positive; 4,490 had fungal culture with 12.3% positive; 4,570 had AFB culture with 1.7% positive; 23,206 had Gram stain, of which 9.0% were positive; and 803 had India Ink stain with 7.7% positive (Table 2 and data not shown). Mean cost of laboratory tests ranged from a high of $ for PCR to a low of $12.40 for glucose (Table 2). The related cost by patient based on the location (outpatient, inpatient ED or after admission) and timing (first or second day after admission) of LP performed was calculated (Table 3 and data not shown). The mean total visit cost was $15,572, of which mean costs of $3,933 were incurred prior to the LP procedure. Higher mean costs were associated with inpatients and the later the 8

10 LP was performed after admission, $2,108 (outpatient) to $30,699 (inpatient, LP second day after admission). Overall, 22.9 % of patients required an ICU stay with an associated average cost of $23,660. The percentage of patients with an ICU stay increased from 20.9 % among patients with LP done in ED to 40.1% in patients with LP done on the second day after admission (Table 3). The mean antimicrobial medication cost and ME-related laboratory test costs were $1,144 and $210, respectively. Since the majority of laboratories do not perform molecular tests in-house, but they are send out tests, the ME-related laboratory test costs was much lower than expected as the reference laboratory testing cost was not captured in the data. The antimicrobial medical cost represented 42% of the total medication cost. Costs for antimicrobials and testing were lower for outpatients and increased across categories: inpatient with ED LP; inpatients with LP 1 day after admission and inpatients with LP 2 days after admission (Table 3). Over half of the study population had a diagnosis of ME due to EV (51.6%), 14.1% to bacteria, 8.3% to herpes viruses group (HSV1/2, VZV, CMV, HHV6), 2.7% to fungi, 1.1% to arbovirus, and 0.8% to other viruses. In addition, 21.4% had no pathogens identified (Table 4). When cost was calculated based on the etiology of ME, patients diagnosed with fungal ME had the highest associated hospitalization cost of $41,459, followed by arbovirus ($39,425), other virus (excludes EV and herpes virus group) ($32,965), and bacterial etiologies ($26,501). The total cost incurred until LP procedure date was highest in other virus group ($6,784), followed by arboviral, bacterial, fungal and herpes virus group. The highest percentage of patients with ICU stay correlated with the other virus group (57.5%), followed by bacteria (54.5%) and arbovirus (54%). 9

11 However, the highest ICU-related cost was for the arbovirus group ($42,713) followed by the fungi group ($33,134). The highest ME-related laboratory test cost was for the other virus group ($359), followed by arboviral ($292) and fungal ($278). ME-related laboratory tests only accounted for a small percentage of the overall laboratory testing cost and was highest in other virus group, followed by arbovirus, fungal, herpes virus and bacterial groups (Table 4). The cost was lower because we could not capture the send-out test costs. The overall medication cost was highest in the fungal group ($14,061), followed by arboviral ($5,756), other virus ($5,154) and bacterial groups ($4,034). Antimicrobial medication cost was highest in the fungi group ($4,800), followed by other virus ($2,126) and enterovirus ($1,796). 10

12 DISCUSSION In this study we described overall hospitalization and diagnosis-related cost of patients who received an LP procedure at hospital settings to rule out or diagnose ME. Our data suggest that the ME management cost is related to the time of diagnosis, ICU stay and the causative agent. The cost sharply increased if the LP was delayed, this may be explained because complications that lead to ICU admission or the patients were too unstable to get an LP and thus it was not the delay in LP per se but the fact that they were in the ICU. The diagnosis of ME is challenging due to the broad clinical differential diagnosis, delay in performing LP and the use of low sensitivity diagnostic tools. ME has a high potential for morbidity and mortality, especially when caused by bacteria and HSV (Beckham et al., 2006, Whitley and Lakeman, 1995). Currently, the majority of patients are managed in a systemic manner based on the probability of acute bacterial meningitis and HSV ME. While the most common etiology causes are considered in the primary diagnosis, some pathogens such as viruses may be missed. This leads to further etiology-specific testing causing a delay in the diagnosis, increased ICU stay, negative patient impact and increased cost (Beckham et al., 2006, Tunkel et al., 2008). A larger number of patients with LP done 2 days after admission had fungal and arboviral infections when compared to those with LP done in the ED (6.3% vs 2.2% and 3.5% vs 0.8%, respectively, Table 3). Fungal and arboviral infections were associated with the highest costs overall when cost was calculated based on ME etiology. This may be explained by the fact that patients with LPs done on the 2nd day had higher costs because of care management and ICU admission. 11

13 A large portion of the hospitalization cost was driven by ICU stay. In the study ICU care was common in patients with ME caused by bacteria, arbovirus or other virus, with more than half of the patients with an ICU admission (Table 4). In the United States costs of ICU stays have markedly increased since the 1990 s representing a higher percentage of the total hospitalization cost (Halpern and Pastores, 2010). Other contributing factors are medication cost and laboratory testing. On average the antimicrobial medication cost was $1,144, with the highest cost if ME was caused by fungi or lower if caused by arbovirus (Table 4). While the laboratory cost represented 8% of the total cost, ME related laboratory tests only represented 1% of the total cost. The low cost of laboratory testing can be attributed in part to the fact that we were not able to capture the cost of the send-out tests. The mean cost for PCR was $140. In most cases, we could anticipate that at least HSV PCR and EV should have been ordered. Because the majority of ME patients are treated in hospital settings, many of the findings in this study can be generalized to other settings. Use of rapid diagnostic tests are associated with lower length of stay, with a direct implication on savings of cost per day for hospitalization (Bauer et al., 2010, Timbrook et al., 2016). Although CSF biochemical tests such as glucose and protein can be used as part of the differential diagnosis, these are not always specific in predicting the pathogen group (bacterial, viral, mycobacterial, etc.) and for patients who have been treated with antibiotics for more than 8 hours prior to LP; generally culture will be sterile complicating the diagnosis (Kanegaye et al., 2001, Michael et al., 2010). The incidence of both pneumococcal and meningococcal meningitis has significantly decreased with vaccination in the US (Cohn et al., 2010, Hsu et al., 2009). 12

14 The majority of the causes of ME are EV (Hasbun et al., 2017). Among patients with EV, early diagnosis has clearly been demonstrated to be associated with reduced antibiotic use, decreased length of stay, fewer additional diagnostic tests (such as CT and MRI), better outcomes and lower cost. Despite documentation that EV PCR results may reduce hospitalization costs, only 3.1% of the ME cases in this study had EV PCR ordered (Ramers et al., 2000). Additionally in institutions where an EV PCR test is ordered, it can take days to get the results back from a reference laboratory, negating the impact of a rapid test result. In this study, use of a PCR test was only 8.9% (Table 2) suggesting that the majority of diagnosed cases were not confirmed by PCR and most likely attributed to a viral etiology only once all routine bacterial and fungal cultures were negative. On site molecular testing should improve diagnosis and management of these infections (Leber et al., 2016). The use of a multiplex rapid assay would provide improved guidance for patient management with fewer requests for other diagnostic examinations, shortened duration of empirical antibiotic treatments especially for those etiologies that antibiotic treatment is not warranted, and reduced length of hospitalization. There are several limitations to our study. First, this is a retrospective observational study; the data source was an administrative hospital discharge database. The descriptions of charge claims were based on each hospital s charge master description, which varies from hospital to hospital. Therefore, for the same test, procedure, or medication, there may be many different expressions in the database with varying specificity of descriptors that could be used as identification and classification. Although broad algorithms were used to maximize the search scope and a thorough review of all records was conducted, underestimation may still exist 13

15 for some variables. Second, the diagnosis of ME and pathogen categorization were based on ICD-9 diagnosis codes. Misclassification may occur due to coding errors or misdiagnosis by clinicians. However, the level of misclassification should be similar across pathogen groups. Third, we used microbiology data submitted by selected hospitals to estimate the testing results for certain CSF tests. Although the study was designed to include all possible results, due to the complexity of the test results recorded, there is a potential that some relevant results may have been excluded. However, the potential omissions should be evenly distributed between positive and negative categories and are likely to not affect the proportion estimates. The cost of laboratory tests did not include send out cost. In summary, our study shows that on average the total visit related costs were $15,772 and that the cost increased if LP procedure was delayed, if ICU stay was needed and if the etiology was fungi, arbovirus, or bacteria. Funding: This work was supported by Medical Affairs Americas, biomérieux. Conflict of interest: S. Duff is a paid consultant to biomérieux and an employee of Veritas Health Economics Consulting; R. Hasbun and J.M. Balada-Llasat are consultants to biomérieux and speakers for BioFire Diagnostics; C.C. Ginocchio is an employee of biomérieux and BioFire Diagnostics; L Zimmer are employees of biomérieux. 14

16 References National Institute of Neurological Disorders and Stroke, Meningitis and Encephalitis FactSheet. alitis_meningitis.htm.. US Department of Labor, Bureau of Labor Statistics. Inpatient hospital services consumer price index. Bauer KA, West JE, Balada-Llasat JM, Pancholi P, Stevenson KB, Goff DA. An antimicrobial stewardship program's impact with rapid polymerase chain reaction methicillin-resistant Staphylococcus aureus/s. aureus blood culture test in patients with S. aureus bacteremia. Clin Infect Dis 2010;51(9): Beckham JD, Tyler KL, Idsa. Initial management of acute bacterial meningitis in adults: summary of IDSA guidelines. Rev Neurol Dis 2006;3(2): Cohn AC, MacNeil JR, Harrison LH, Hatcher C, Theodore J, Schmidt M, et al. Changes in Neisseria meningitidis disease epidemiology in the United States, : implications for prevention of meningococcal disease. Clin Infect Dis 2010;50(2): Halpern NA, Pastores SM. Critical care medicine in the United States : an analysis of bed numbers, occupancy rates, payer mix, and costs. Crit Care Med 2010;38(1): Hasbun R, Bijlsma M, Brouwer MC, Khoury N, Hadi CM, van der Ende A, et al. Risk score for identifying adults with CSF pleocytosis and negative CSF Gram stain at low risk for an urgent treatable cause. J Infect 2013;67(2): Hasbun R, Rosenthal N, Balada-Llasat JM, Chung J, Duff S, Bozzette S, et al. Epidemiology of Meningitis and Encephalitis in the United States from Clin Infect Dis Hsu HE, Shutt KA, Moore MR, Beall BW, Bennett NM, Craig AS, et al. Effect of pneumococcal conjugate vaccine on pneumococcal meningitis. N Engl J Med 2009;360(3): Kanegaye JT, Soliemanzadeh P, Bradley JS. Lumbar puncture in pediatric bacterial meningitis: defining the time interval for recovery of cerebrospinal fluid pathogens after parenteral antibiotic pretreatment. Pediatrics 2001;108(5): Khoury NT, Hossain MM, Wootton SH, Salazar L, Hasbun R. Meningitis with a negative cerebrospinal fluid Gram stain in adults: risk classification for an adverse clinical outcome. Mayo Clin Proc 2012;87(12): Leber AL, Everhart K, Balada-Llasat JM, Cullison J, Daly J, Holt S, et al. Multicenter Evaluation of BioFire FilmArray Meningitis/Encephalitis Panel for Detection of Bacteria, Viruses, and Yeast in Cerebrospinal Fluid Specimens. J Clin Microbiol 2016;54(9): Michael B, Menezes BF, Cunniffe J, Miller A, Kneen R, Francis G, et al. Effect of delayed lumbar punctures on the diagnosis of acute bacterial meningitis in adults. Emerg Med J 2010;27(6): Ramers C, Billman G, Hartin M, Ho S, Sawyer MH. Impact of a diagnostic cerebrospinal fluid enterovirus polymerase chain reaction test on patient management. JAMA 2000;283(20): Richie MB, Josephson SA. A Practical Approach to Meningitis and Encephalitis. Semin Neurol 2015;35(6):

17 Romero JR, Newland JG. Viral meningitis and encephalitis: traditional and emerging viral agents. Semin Pediatr Infect Dis 2003;14(2): Thigpen MC, Whitney CG, Messonnier NE, Zell ER, Lynfield R, Hadler JL, et al. Bacterial meningitis in the United States, N Engl J Med 2011;364(21): Timbrook TT, Morton JB, McConeghy KW, Caffrey AR, Mylonakis E, LaPlante KL. The Effect of Molecular Rapid Diagnostic Testing on Clinical Outcomes in Bloodstream Infections: A Systematic Review and Meta-analysis. Clin Infect Dis Tunkel AR, Glaser CA, Bloch KC, Sejvar JJ, Marra CM, Roos KL, et al. The management of encephalitis: clinical practice guidelines by the Infectious Diseases Society of America. Clin Infect Dis 2008;47(3): Whitley RJ, Lakeman F. Herpes simplex virus infections of the central nervous system: therapeutic and diagnostic considerations. Clin Infect Dis 1995;20(2): Figures and table TABLES Table 1: Patient characteristics of the study population Variables N % # of Unique Patients 26, Sex a Female 14, Male 12, Health Insurance Type Private insurance 12, Public insurance 10, Uninsured 3, Other Patient type Inpatient 24, Outpatient 2, ME etiology b Enterovirus 13, Bacteria 3, Herpes virus c 2, Fungi Arbovirus Other viruses Unknown pathogens 4,

18 Non-ME a Unknown (n=3) b Based on discharge or admitting diagnosis (if no discharge diagnosis of ME). Excludes 41 outpatients with LP not performed in ED c HSV 1/2, VZV, CMV, HHV6 17

19 Table 2. Number of tests from CSF for which comparable tests orders could be determined a Variables N % Cost (2015 U.S. dollars, mean ± STD) Gram stain 23, ± 27.3 Glucose 16, ± 13.6 Protein 16, ± 14.0 Cell count and differential 13, ± 95.1 Bacterial culture 14, ± 21.0 AFB culture 4, ± 32.0 Fungal culture 4, ± 22.5 Antibody tests b 3, ± 95.8 Any PCR test c 2, ± Cryptococcal antigen test 1, ± 18.9 Viral culture 1, ± 41.0 India ink stain ± 11.7 Other antigen tests ± 29.9 a Due to major differences in coding of tests not all were captured. b Among all adult patients who had antibody tests, 44.4% were tested for WNV, 15% Lyme disease, 12.1% Coccidioides, 10% HSV, 1.4% Cryptococcus, 0.9% CMV, 0.9% VZV, 22.8% other. c Among all adult patients who had PCR test, 12.1% were tested for HSV, 5.1% EV, 1.5% Lyme disease, 1.7% WNV, 1.8% AFB, 0.3% EBV, 0.1% HHV, 1.4% other. 18

20 Table 3. Related cost by timing of LP performed among the study population Total Outpatients with Inpatients with Inpatients with Inpatients with LP LP in ED a LP in ED b LP 1 day after 2 day after admission c admission d Unique Patients 26,429 e 2,297 18,148 4,205 1,738 Total Visit Cost (Mean ± STD) 15,572 ± 2,108 ± 13,747 ± 24,670 ± 27,168 2,060 23,497 37,150 Total Cost incurred till LP procedure day (Mean ± STD) Number of patients with an ICU stay (%) 3,933 ± 3,611 6,064 (22.9%) ICU-related cost (Mean ± STD) 23,660 ± 33,668 Medication Treatment Cost (Mean ± STD) Antimicrobial medication cost (Mean ± STD) Diagnostic Laboratory Testing Cost (Mean ± STD) ME-related laboratory tests Cost (Mean ± STD) 2,706 ± 7,567 1,144 ± 4,052 1,222 ± 1, ± 244 1,579 ± 1,243 a Discharge diagnosis: Bacteria (48), herpes virus (25), enterovirus (1,664), other virus (1), fungi (10), unknown pathogens (509), Non-ME diagnosis (40). Based on primary and secondary diagnosis coding or transfer to different facility b Discharge diagnosis: Bacteria (2,630), herpes virus (1,697), arbovirus (141), enterovirus (9942), other virus (106), fungi (398), unknown pathogens (2,538), Non-ME diagnosis (696) c Discharge diagnosis: Bacteria (748), herpes virus (333), arbovirus (89), enterovirus (1,390), other virus (68), fungi (201), unknown pathogens (1,227), Non-ME diagnosis (149) d Discharge diagnosis: Bacteria (265), herpes virus (128), arbovirus (61), enterovirus (451), other virus (38), fungi (110), unknown pathogens (653), Non-ME diagnosis (32) 3,258 ± 2,699 N/A 3,799 (20.9%) N/A 20,903 ± 160 ± ± ± ± ,118 2,381 ± 6,470 1,063 ± 4,081 1,129 ± 1, ± 227 6,005 ± 4,256 1,568 (37.3%) 26,714 ± 32,375 4,374 ± ,512 ± 4,269 1,741 ± 2,023 30,699 ± 37,525 9,087 ± 5, (40.1%) 31,818 ± 41,912 4,879 ± ,873 ± 4,418 2,115 ± 250 ± 273 2, ± 360 e Includes 41 outpatients with LP not performed in ED STD- Standard deviation; N/A- Not applicable 19

21 Table 4. Costs for the study population with ME by pathogen type Total Bacteria Enterovirus Herpes Virus b Arbovirus Other Virus Fungi Unknown pathogens Number of Unique Patients 26,429 a 3,692 13,463 2, ,944 Hospitalization cost Mean ± 15,572 ± 26,501 ± 7,909 ± 15,100 ± 39,425 ± 32,965 ± 41,459 ± 23,386 ± STD) 27,168 30,449 11,384 18,701 49,348 40,685 52,148 Cost incurred till LP (Mean ± STD) Patients with ICU stay n (%) ICU-related cost (Mean ± STD) Total medication cost (Mean ± STD) Antimicrobial medication cost (mean ± STD) Diagnostic Laboratory Testing Cost (Mean ± STD) ME-related laboratory tests (Mean ± STD) 3,933 ± 3,611 6,064 (22.9%) 23,660 ± 33,668 2,706 ± 7,567 1,144± 4,052 1,222 ± 1, ± 244 a 921 patients were discharged with Non-ME diagnosis; STD- Standard deviation b HSV 1/2, VZV, CMV, HHV6 5,329 ± 4,279 2,013 (54.5%) 24,433 ± 28,491 4,034 ± 6,124 1,619± 3,078 1,727 ± 1, ± 245 3,011 ± 2,388 1,271 (9.44%) 15,200 ± 22,301 1,202 ± 3,184 1,796± 8, ± ± 206 3,874 ± 2, (18.8%) 20,536 ± 24,497 3,111 ± 9,381 1,562± 2,243 1,154 ± 1, ± 304 5,645 ± 3, (54%) 42,713 ± 45,036 5,756 ± 8, ± 1,761 2,490 ± 2,363 6,784 ± 5, (57.5%) 29,466 ± 29,397 5,154 ± 7,595 2,126± 4,713 2,322 ± 2,843 5,252 ± 4, (28.8%) 33,134 ± 60,978 14,061 ± 20,381 4,800± 12,861 2,417 ± 2,266 40,197 5,118 ± 4,904 1,743 (35.3%) 26,897 ± 40,445 3,938 ± 10,654 1,233± 2,919 1,694 ± 292 ± ± ± 312 2, ±