In 1937, West Nile virus (WNV) was isolated in Uganda s

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1 West Nile virus and the 2012 outbreak: The Baylor University Medical Center experience Adan Mora Jr., MD, Mariangeli Arroyo, MD, Kyle L. Gummelt, DO, MPH, Gates Colbert, MD, Anna L. Ursales, MD, Michael J. Van Vrancken, MD, MPH, George J. Snipes, MD, Joseph M. Guileyardo, MD, and Cristie Columbus, MD West Nile virus (WNV) has been responsible for multiple outbreaks and has shown evolution in its clinical manifestation. The Centers for Disease Control and Prevention has provided diagnostic criteria in classifying the variety of WNV infection; however, application of these criteria can prove challenging during outbreaks, and understanding the array of presentations and patient population is clinically important. In this article, we present the challenges encountered during the 2012 outbreak at one institution. In 1937, West Nile virus (WNV) was isolated in Uganda s West Nile region (1). Initial outbreaks described self-limited febrile illnesses with polyarthralgias and rash (2, 3). After 1990, outbreaks reported neurological symptoms (4). In 1999, the first US epidemic was in New York City, resulting in 59 encephalitis cases and 7 deaths (5). The most common presentation is West Nile fever (WNF), a self-limited illness with fever, fatigue, myalgia, rash, and headache lasting 3 to 10 days. Patients may experience persistent fatigue, difficulty concentrating, and a delayed return to baseline functioning (6). The virus may penetrate the central nervous system (CNS), causing several forms of West Nile neuroinvasive disease (WNND). West Nile meningitis, characterized by fever, headache, nuchal rigidity, and cerebrospinal fluid (CSF) pleocytosis, is associated with favorable outcomes (7 9). Most feared, West Nile encephalitis varies from mild confusion to severe encephalopathy, leading to coma or death in 10% to 20% of cases (7). Symptoms include myoclonus, parkinsonism, extrapyramidal symptoms, ataxia, cranial nerve involvement, altered consciousness, and seizures (9 11) resulting in prolonged hospital courses requiring mechanical ventilation and intensive care. WNND is associated with long-term morbidity, delayed physical and cognitive recovery, and prolonged disability (12). Baylor University Medical Center (BUMC) at Dallas cared for many WNV-infected patients during the 2012 epidemic. This study was conducted to explore challenges faced and lessons learned. METHODS A retrospective medical record review identified cases of WNV cases in the emergency department and inpatient service at BUMC from January to December Cases were Proc (Bayl Univ Med Cent) 2015;28(3): identified using two databases. The hospital s reference laboratory (med fusion) was queried for positive results that included serum or CSF WNV IgM and IgG antibodies and WNV polymerase chain reaction (PCR) tests. Our laboratory used the IgM Capture DxSelect TM enzyme-linked immunosorbent assay and Focus Diagnostics IgG DxSelect TM enzyme-linked immunosorbent assay for qualitative detection of WNV IgM and IgG antibodies. Positive results were submitted to the Texas Department of State Health Services for confirmatory testing. Tests for WNV PCR were submitted to ARUP Laboratories, which uses qualitative real-time PCR to test serum and CSF in accordance with Roche Molecular Systems methods (13). The institutional administrative coding database was crossreferenced for diagnoses of WNV infection. Patients with prior WNV disease or only WNV IgG antibodies whose clinical picture wasn t compatible with acute disease were excluded. Extracted data included demographics, comorbidities, symptoms, relevant physical examination findings, admission location, complications, diagnostic test results, and disposition. Immunosuppression was considered if records documented another disease known to affect the immune system or immunosuppressive therapy with systemic steroids (prednisone >20 mg or equivalent steroid longer than 2 weeks), biologic agents, or other immunomodulatory drugs. Cases were classified as confirmed WNF, probable WNF, confirmed WNND, or probable WNND per case definition criteria of the Centers for Disease Control and Prevention (CDC) (14). To address variable clinician evaluation and capture patients not fulfilling CDC definitions whose composite clinical and laboratory data suggested WNF or WNND, categories of possible WNF and WNND were created. For example, some patients not meeting the definition of fever had laboratory evidence in serum or CSF supporting active WNV infection. The study was approved by the institutional review board of BUMC. From the Division of Pulmonary Disease (Mora), Department of Internal Medicine (Arroyo, Gummelt, Colbert, Ursales), Department of Pathology (Van Vrancken, Snipes, Guileyardo), and Division of Infectious Diseases (Columbus), Baylor University Medical Center at Dallas. Corresponding author: Adan Mora Jr., MD, Division of Pulmonary Disease, Department of Internal Medicine, Baylor University Medical Center at Dallas, 3500 Gaston Avenue, Dallas, TX ( adam.mora@baylorhealth.edu). 291

2 RESULTS Sixty-eight cases were identified and 13 eliminated by our exclusion criteria. Fifty-five cases were evaluated: 12 comprised the WNF group (7 probable, 5 possible, and none confirmed), and 43 comprised the WNND group (7 confirmed, 29 probable, and 7 possible). Patient characteristics and comorbidities are summarized in Table 1. The age range was 19 to 84 years, with a mean of 53.4 years. Most patients were white, non-hispanic men. Body mass index ranged from 15.7 to 62.4 kg/m 2, with a mean of 28.8 kg/m 2. The most common comorbid condition was hypertension. Presenting complaints and findings are outlined in Table 2. Subjective fevers were reported by 52 patients (42 had a documented fever of >100.4 F), classifying 10 patients as possible WNV infection (5 WNF, 5 WNND). Other fi ndings were headache, altered mental status, hyponatremia, and gastroenteritis. Less common were seizures, acute kidney injury, acute respiratory failure, elevated transaminases, elevated total bilirubin, acute flaccid paralysis, rhabdomyolysis, tremors, myoclonus, and atrial fibrillation. In the WNND group, 26 had headache, 27 had altered mental status, 12 had seizures, and 3 had acute flaccid paralysis. The most commonly reported symptoms in the WNF group were headache and gastrointestinal symptoms. In this group, fever >100.4 F was documented in 7 patients and altered mental status was an uncommon presentation. Table 2 also outlines diagnostic laboratory findings. Serum WNV IgM antibodies were positive in most patients. Two patients (both WNND) had detectable total WNV antibodies that weren t fractionated into IgM or IgG components, deeming them possible WNV infection. Serum PCR WNV was performed in one patient and was undetectable. Serum arbovirus panels were obtained in six patients and were negative. In the WNND group, a serum WNV IgM test was positive in 35 patients, negative in 2, and not obtained in 6 (including the two with positive total unfractionated WNV antibody). Serum WNV PCR was not obtained in any WNND patient. However, all had clinical neurological findings compatible with WNND, as defined by CDC clinical criteria (Table 3). Fortythree patients underwent lumbar puncture. Cell counts were available on 42, and 37 had pleocytosis. In the WNND group, cell counts were available in 37, and 35 had pleocytosis. Thirtytwo patients had CSF analysis for WNV IgM, and 19 had detectable CSF WNV IgM antibodies. Three had a positive CSF WNV PCR, but the test was only ordered in 14. CSF WNV IgG antibody testing was performed in 8 of the 43 patients; only one patient tested positive. Thirty-two patients (25 WNND) were initially admitted to a medicine floor; 19 (17 WNND) to the intensive care unit, and 4 (1 WNND) were seen and discharged in the emergency department. The mean length of stay for all was 7.7 days (WNND, 8.9 days; WNF, 3.2 days). In the WNF group, 11 were discharged home and one to a rehabilitation facility. In contrast, for WNND, 23 were discharged home, 7 to a rehabilitation unit, 2 to a long-term acute care facility, 2 to a skilled nursing facility, and 9 died. The mortality rate was 21%. Of all Table 1. Demographic characteristics of 55 West Nile patients treated at Baylor University Medical Center in 2012 Category Variable N % Age (years) % % % % % % % Race White 30 55% Black 11 20% Hispanic 14 26% Asian 0 0% Sex Male 36 65% Female 19 35% Body mass index < % % % % > % Not done 5 9% Length of stay (days) 0 4 7% % % % % % % Admission status Emergency room 4 7% Medical/surgical floor 32 58% Intensive care unit 19 35% Discharge status Home 34 62% Long-term acute care 2 4% Skilled nursing facility 2 4% Rehabilitation unit 8 15% Died, no autopsy 5 9% Died, with autopsy 4 7% History Hypertension 33 60% Diabetes 38 69% Transplant 1 2% Chronic kidney disease 6 11% Immunocompromised 7 13% Current conditions Hypertension 22 40% Diabetes mellitus 17 31% Transplant recipient 1 2% Chronic kidney disease/ 6 11% end-stage renal disease Immunocompromised 7 13% 292 Baylor University Medical Center Proceedings Volume 28, Number 3

3 Table 2. Signs and symptoms and laboratory data for 55 West Nile patients treated at Baylor University Medical Center in 2012 Variable Positive Total reported Percent* Subjective fevers % Objective fever >100.4 F % Any fever % Elevated WBC on CSF % Headache % AMS/encephalopathy % Acute flaccid paralysis % Myoclonus % Tremors % Rhabdomyolysis % Atrial fibrillation % Elevated total bilirubin % Acute kidney injury % Acute respiratory failure % Transaminitis % Gastroenteritis % Epididymitis % Hyponatremia Serum sodium <120 meq/l % Sodium meq/l % Sodium meq/l % Sodium meq/l % Sodium meq/l % Sodium >145 meq/l % Laboratory results Serum antibody screen % Serum IgM % Serum IgG % Serum PCR 0 1 0% Serum arbovirus 0 6 0% CSF IgM % CSF IgG % CSF PCR % CSF arbovirus 0 6 0% *The percentage reflects the total number of positive responses among those for whom data were available (which was not always the full group of 55 patients). AMS indicates altered mental status; CSF, cerebrospinal fluid; PCR, polymerase chain reaction; WBC, white blood cells. WNV deaths in the four-county area, 24% were hospitalized at BUMC. Among the 9 patients who died, 8 were older than 50 years of age; 6 were men, 4 were white, 3 were Hispanic, and 2 were black. Six had hypertension, 6 had diabetes mellitus, 5 had chronic or end-stage renal disease, and 3 were immuno- Table 3. Comparison of cases with West Nile fever and West Nile neuroinvasive disease WNF WNND Confirmed cases 0 7 Probable cases 7 29 Possible cases 5 7 Total Mean age (years) Mean body mass index (kg/m 2 ) Symptoms Fever 5 35 Headache 6 26 Gastrointestinal illness 5 19 Altered mental status 1 27 Seizures 0 11 Acute flaccid paralysis 0 3 Serum WNV IgM positive Serum WNV IgM negative 1 2 Serum WNV IgM not drawn 0 6 CSF WNV IgM positive 0 19 CSF WNV IgM negative 4 9 CSF WNV IgM not drawn 8 15 CSF WNV PCR positive 0 3 CSF WNV PCR negative 1 28 Mean length of stay (days) Discharge status Home Rehabilitation facility 1 7 Long-term care facility 0 2 Skilled nursing facility 0 2 Death 0 9 Mortality rate (%) 0% 21% compromised. Several patients had multiple comorbidities. All presented with altered mental status and subjective fever (8 documented a fever of F). Eight were admitted to the intensive care unit. Seven had acute respiratory failure requiring mechanical ventilation, and six had seizures. DISCUSSION This study highlights WNV outbreak challenges. One challenge was related to case classification, given strict CDC criteria (14). Twenty-two percent of patients didn t fulfill CDC case definitions for confirmed or probable WNND or WNF (Table 3). They lacked a documented fever >100.4 F and/or specific confirmatory testing. Elderly patients and those with renal failure or receiving corticosteroids may have had compromised febrile response mechanisms (15, 16). Another challenge was underutilization of nucleic acid amplification techniques early in July 2015 West Nile virus and the 2012 outbreak: The Baylor University Medical Center experience 293

4 acute illness or in immunosuppressed populations. Such testing can be costly, and with decreasing reimbursement, physicians may be reluctant to order molecular diagnostics when effective therapeutic options are lacking. Additionally, tests measuring neutralizing antibodies aren t widely available (limited to state departments of health and the CDC). Physician unfamiliarity with the presentations of WNV illness, coupled with the lack of standardized testing protocols for suspected disease, contributed to uncertainty in the classification of some cases. To avoid excluding potential cases, we employed a category of possible WNV infection as described previously. We suggest the CDC adopt a defi nition of possible WNV infection for reporting and potentially therapeutic purposes. For case definition, arboviral testing should be limited to known regional endemic viruses. The presence of endemic viruses in sentinel populations could be utilized in CDC case definitions. In the absence of active endemic viruses in humans or sentinel populations, no further arboviral testing is necessary. For example, St. Louis encephalitis virus infections previously endemic to our area were not detected in humans, sentinel fl ocks, or mosquito pools during the 2012 season (17, 18). We suggest the CDC laboratory diagnostic criterion negative arboviral serologies for endemic arboviruses be revised to reflect the absence of other endemic arboviruses in mosquitoes and sentinel birds in the affected geographic area during an epidemic. Additional difficulties involved distinguishing between true WNND and WNF with nonspecifi c neurologic symptoms. Determining whether WNV infection was a primary or contributory cause of death was problematic. Although most of the autopsied patients had CNS lesions that were clearly sufficient to explain death, one patient did not have well-developed CNS pathology. The literature cites evidence that systemic WNV infection may cause direct injury to organs, exacerbating preexisting diseases (19 21). This may complicate the diagnostic evaluation when attempting to decipher what is or is not attributable to WNV infection. WNV may contribute to the death of patients with significant underlying comorbidities in the absence of definitive CNS involvement. Data published by Schanzer et al reviewed the potential contributory role of influenza and found many comorbidities to be associated with influenza-attributed deaths, particularly pulmonary and cardiac diseases (21). It is important to realize that WNV may have systemic implications. We caution that misidentification of potentially treatable conditions could delay appropriate therapy. Furthermore, historical data review found distribution differences in WNF and WNND cases in 2003 versus 2012 (22, 23). In 2003, the WNF:WNND ratio was approximately 2.4:1; in 2012, this ratio was approximately 1:1. Both observations raise the possibility that the virus may have become more neurotropic due to viral mutation and genetic drift. Other possibilities include changes in testing patterns with improved detection related to patient and physician awareness and immunity of the population at risk. Of concern, despite increased awareness and prevention with DEET, mortality has not substantially decreased. Data analysis suggests opportunities to improve our response to outbreaks. Lessons learned include the need to 1) remain vigilant for the diagnosis of WNV; 2) educate staff in recognizing real-world manifestations of WNV infection, which doesn t neatly lend itself to published criteria for diagnosis; 3) develop standardized diagnostic testing algorithms; 4) develop recommendations for multisystem supportive care in WNF and WNND patients; and 5) research strategies for better detection, prevention, and treatment, including refined molecular tools for viral identification. Plans are currently under way at BUMC to optimize response to future outbreaks. Some activities involve developing standardized testing protocols and guidelines for the care of patients with possible WNV infection. However, further studies are needed as we search for more effective diagnostic, supportive, and therapeutic measures. 1. Smithburn KC, Hughes TP, Burke AW, Paul JH. A neurotropic virus isolated from the blood of a native of Uganda. Am J Trop Med Hyg 1940;20: Petersen LR, Roehrig JT. West Nile virus: a reemerging global pathogen. Emerg Infect Dis 2001;7(4): Murgue B, Murri S, Triki H, Deubel V, Zeller HG. West Nile in the Mediterranean basin: Ann N Y Acad Sci 2001;951: Klein C, Kimiagar I, Pollak L, Gandelman-Marton R, Itzhaki A, Milo R, Rabey JM. Neurological features of West Nile virus infection during the 2000 outbreak in a regional hospital in Israel. 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