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Influenza Testing, Diagnosis, and Treatment in the Emergency Department in 2009-2010 and 2010-2011

2013; Wiley; Volume: 20; Issue: 8 Linguagem: Inglês

10.1111/acem.12175

1553-2712

Timothy R. Peters, Cynthia K. Suerken, Beverly M. Snively, James E. Winslow, Milan Nadkarni, Scott B. Kribbs, Katherine A. Poehling,

Viral Infections and Vectors

The objective was to describe patterns of rapid influenza test ordering, diagnosis of influenza, and antiviral prescribing by the treating physician for children and adults presenting to emergency departments (EDs) with fever and acute respiratory symptoms in Winston-Salem, North Carolina, over two influenza seasons. The authors prospectively enrolled patients presenting to the ED with fever and acute respiratory symptoms for two influenza seasons: H1N1 pandemic of September 2009 through mid-May 2010 and November 2010 through April 2011. Enrolled patients had nose or and throat swabs obtained and tested for influenza by viral culture and polymerase chain reaction (PCR) testing. Demographic information and medical history were obtained by patient or guardian report. Testing, treatment, and discharge diagnosis from the ED visit, as well as medical history and insurance status, were ascertained from chart review. Among 2,293 eligible patients approached, 1,657 (72%) were enrolled, of whom 38% were younger than 18 years, 47% were 18 to 49 years, and 15% were 50 years of age and older. Overall, 14% had culture- or PCR-confirmed influenza. The odds of 1) rapid influenza test ordering, 2) a physician diagnosis of influenza, and 3) prescribing antiviral treatment during the ED visit were fourfold higher among patients with than without culture- or PCR-confirmed influenza. The odds of rapid influenza test ordering were threefold lower in 2009/2010 than 2010/2011, whereas the odds of physician diagnosis of influenza and antiviral prescriptions were 2- and 3.5-fold higher, respectively. In 2009/2010 compared to 2010/2011, the odds of rapid influenza test ordering were lower, whereas the odds of influenza-specific discharge diagnoses and antiviral prescriptions were higher among patients presenting to the ED with culture/PCR-confirmed influenza. These results demonstrated a gap between clinical practice and recommendations for the diagnosis and treatment of influenza from the Centers for Disease Control and Prevention (CDC). Objetivos: Describir las pautas en la solicitud del test rápido de la gripe, el diagnóstico de gripe y la prescripción de tratamiento antiviral por el médico que atiende a niños y adultos que acuden a los servicios de urgencias (SU) con fiebre y síntomas respiratorios agudos en Winstom-Salem, Carolina del Norte, a lo largo de dos temporadas de gripe estacional. Se incluyeron pacientes de forma prospectiva que acudieron al SU con fiebre y síntomas respiratorios agudos en dos pandemias de gripe H1N1 estacional de septiembre a mitad de mayo de 2010, y de noviembre de 2010 hasta abril de 2011. Se obtuvo de los pacientes incluidos una muestra de secreciones de la nariz y/o la garganta y se analizó para gripe meditante cultivo viral y el test de la reacción en cadena de la polimerasa (PCR, polymerase chain reaction). Se obtuvo la información demográfica y la historia médica del paciente o tutor. Las pruebas diagnósticas, el tratamiento y el diagnóstico al alta de la visita al SU, así como la historia clínica y el estado del seguro, se verificaron mediante la revisión de las historias clínicas. Entre los 2.293 pacientes elegibles iniciales, se incluyeron 1.657 (72%). El 38% eran menores de 18 años, el 47% tenía entre 18 y 49 años, y el 15% tenía 50 años o más. Del total, el 14% tuvo un cultivo o PCR que confirmó la gripe. La razón de ventajas (odds ratio, OR) de solicitar un test rápido de gripe, de realizar un diagnóstico clínico de gripe, y de prescribir tratamiento antiviral durante la visita al SU fue cuatro veces mayor entre los pacientes con cultivo o PCR confirmado para gripe en relación con aquéllos que no. Las OR del test rápido de gripe fue tres veces menor en 2009/2010 que en 2010/2011, mientras que la OR de diagnóstico clínico de gripe y las prescripciones de antiviral fueron 2 y 3,5 veces mayores, respectivamente. En 2009/2010, en comparación con 2010/2011, la OR para la solicitud del test rápido de la gripe fue menor, mientras que las OR de diagnóstico al alta específico de gripe al alta prescripciones de antiviral fueron mayores entre los pacientes que acudieron al SU con cultivo o PCR confirmados para gripe. Estos resultados demostraron una laguna entre la práctica clínica y las recomendaciones de los Centers for Disease Control and Prevention para el diagnóstico y el tratamiento de la gripe. Influenza virus causes many emergency department (ED) visits each year.1-3 Despite its prevalence, influenza illness can be challenging to specifically diagnose. The timing and duration of influenza season vary annually, and influenza virus typically circulates concurrently with other respiratory viruses. Clinical symptoms associated with influenza infection are nonspecific and can overlap with those caused by other viral illnesses,4-8 and clinical diagnosis of influenza has low sensitivity.9-13 Many rapid influenza diagnostic tests are available and can assist in making a timely diagnosis. Rapid influenza diagnostic tests have been shown to effect clinical decision making in the ED, including fewer diagnostic tests, fewer antibiotic prescriptions, shorter length of stay, and more antiviral prescriptions.14-17 However, rapid influenza diagnostic tests with low sensitivity are prone to false-negative results, and the test characteristics are most favorable when influenza is prevalent.18-20 Limited sensitivity of rapid influenza tests for the 2009 H1N1 influenza A pandemic was reported.21-23 Variations in the use of rapid influenza tests and prescribing antiviral treatment are known,2, 24-26 yet a greater understanding of practice patterns in the ED setting could inform efforts to improve timely influenza diagnosis and treatment. Two neuraminidase inhibitors, oseltamivir and zanamivir, received U.S. Food and Drug Administration (FDA) approval in 1999 for treatment of influenza A and B infections. When prescribed early in the disease, these medications reduce the duration of influenza symptoms, with greater benefit seen for persons 50 years of age and older, and persons with high-risk conditions, than for younger healthy persons.27-33 Healthy persons treated with neuraminidase inhibitors had 1- to 2.5-day reductions in symptom days, compared to those treated with placebo within 48 hours of onset of influenza symptoms.27-29 Observational studies have also demonstrated benefits of neuraminidase inhibitors initiated after 48 hours of symptoms among persons with high-risk medical conditions and hospitalized persons.34 Yet, neuraminidase inhibitors have side effects,35 and influenza virus can develop resistance to antiviral medications.36-39 Also, cost–effectiveness and cost–benefit analyses have led to differing conclusions about the benefits of testing and treatment depending on assumptions such as patient age and prevalence of influenza.40-45 During the H1N1 influenza A pandemic, recommendations for antiviral therapy with neuraminidase inhibitors were expanded46 and included an emergency use authorization from the FDA for the use of oseltamivir for children younger than 1 year of age from September 25, 2009, through June 23, 2010.47 These recommendations, including antiviral treatment of children younger than 1 year of age with suspected influenza, were reaffirmed for the 2010/2011 influenza season, characterized by widespread circulation of seasonal influenza A (H3N2) and B viruses, as well as 2009 pandemic strain H1N1 influenza A. However, the emergency use authorization from the FDA for oseltamivir among children younger than 1 year of age was not reissued.48 Given the known challenges to making an accurate and timely diagnosis of influenza and the limitations of rapid influenza tests, it is not known how clinicians in the ED are interpreting and implementing these recommendations. Hence, we sought to describe rapid influenza test ordering, diagnosis of influenza, and antiviral prescribing by treating physicians for children and adults presenting with fever and acute respiratory symptoms to both EDs in Winston-Salem, North Carolina, from 2009 through 2011. We performed prospective surveillance in the 2009/2010 and 2010/2011 influenza seasons in the two EDs serving more than 94% of all Forsyth County, North Carolina, residents. Surveillance for patients presenting with fever and acute respiratory symptoms was conducted from September 1, 2009, through May 19, 2010, and encompassed the entire peak pandemic H1N1 influenza A season.49 In 2010/2011, surveillance was conducted from November 1, 2010, through April 30, 2011, and encompassed the entire influenza season.48 All enrolled patients provided written informed consent or assent when appropriate. This study was approved by the Wake Forest School of Medicine Institutional Review Board and by an authorization agreement between the institutional review boards of Forsyth Medical Center and Wake Forest School of Medicine. Children and adults were eligible for enrollment if they presented to the ED with any of the following symptoms: fever, cough, nasal congestion, difficulty breathing, earache, sore throat, or wheezing. Patients with only fever and an identified nonrespiratory source of fever, e.g., abscess or urinary tract infection, were excluded. Eligible patients resided in Forsyth County or one of its seven contiguous North Carolina counties and provided consent in English or Spanish. Eligible patients were systematically approached during daytime hours Monday through Thursday. Enrolled patients had nasal and throat swabs collected for culture- or polymerase chain reaction (PCR) test–confirmed influenza testing. A standardized questionnaire to ascertain demographic characteristics and medical history was administered to enrolled patients or their guardians. A medical chart review for the enrollment visit was reviewed by a trained research assistant. Enrolled patients had nasal and throat swabs collected, placed in transport medium, and refrigerated until they were processed within 24 hours of collection. Specimens were cultured for influenza virus using standard direct fluorescence antibody assays (R-Mix Too culture system, Diagnostic Hybrids, Athens, OH).6 From each specimen, extracted RNA was tested by reverse-transcription PCR for 2009 pandemic H1N1 influenza A, seasonal influenza A, and influenza B. All specimens had positive RNA controls with human RNase P. All reverse-transcription PCR protocols and probe and primer sequences were provided by the Centers for Disease Control and Prevention (CDC; Virus Surveillance and Diagnostics Branch, Influenza Division, Atlanta, GA) and were synthesized according to CDC specifications (Biosearch Technologies, Novato, CA). Results from both viral culture and PCR were evaluated and resulted in a standard of combining of the culture and PCR results to define influenza infection.50 The performance characteristics of rapid influenza tests have been determined by comparing their results with those of culture and PCR for influenza.51, 52 Consistent with this standard definition, specimens that were positive by viral culture or PCR for influenza were classified as culture/PCR-confirmed influenza. Specimens were classified as not having culture/PCR-confirmed influenza if influenza virus was not detected by viral culture or PCR. The medical chart for the enrollment visit was reviewed by trained research assistants. Rapid influenza test ordering, discharge diagnosis, and medications prescribed by the treating physician during the ED visit, as well as medical history and insurance status, were recorded using a standardized chart review form. During both study seasons, neuraminidase inhibitors were the only recommended antiviral treatment for influenza.46 The demography of children includes children younger than 1 year (age at high risk for complications and emergency FDA approval for oseltamivir in 2009/2010 only), between 1 and 2 years (age at high risk for complications with FDA approval for osteltamivir), 2 to 4 years (preschool, with age-based influenza vaccine recommendations since 2006), and 5 to 17 years (school-age, with age-based influenza vaccine recommendations since 2008). High-risk medical conditions included all conditions with specific 2009/2010 influenza vaccine indications: heart disease, metabolic diseases, pulmonary disease, renal dysfunction, hemoglobinapathies, immunodeficiency, cognitive or neurologic conditions that can compromise respiratory functioning, and children on long-term aspirin therapy.53, 54 The presence of high-risk medical conditions was determined by either patient/guardian report or by documentation in the medical chart for that ED visit. The primary outcome measures were the presence or absence of rapid influenza test ordering, diagnosis of influenza, or antiviral prescribing by the treating physician during the enrolled ED visit. For each primary outcome measure, a priori covariates included year, culture/PCR-confirmed influenza, age group (child, adult), sex, county (Forsyth/other), insurance (public only/any private/none), hospitalized, high-risk condition, rapid influenza test ordered, influenza vaccination status, and the other outcome measures. These covariates were determined a priori by previous research and collective clinical experience; children and adults were compared to ensure at least 10 events per covariate in each analysis.2, 55-57 All variables were analyzed by chi-square test to show the results for each season because these two seasons were so different. Multivariate logistic regression analyses were performed to identify independent factors associated with rapid influenza test ordering, diagnosis of influenza, and antiviral prescribing during the ED visit with the inclusion of all covariates. Multivariate analyses with and without influenza vaccination status were evaluated, but because the results were similar, influenza vaccination status was not included in the manuscript. A secondary multivariate analysis including symptom days (≤2 days, >2 days) was performed, and excluded county, which was not significant in any analysis, to keep the ratio of events to covariates > 10.57 All models were evaluated by the Homer-Lemeshow goodness-of-fit test. A p < 0.05 was considered statistically significant and was not adjusted for multiple comparisons. Analyses were performed using STATA 8.1 (StataCorp LP, College Station, TX) and SAS 9.2 (SAS Institute Inc., Cary, NC). A total of 2,293 eligible patients presenting to either ED with fever or acute respiratory symptoms were approached, and 1,657 (72%) were enrolled, comprising the study population. A total of 807 (49%) patients were enrolled from September 1, 2009, through May 19, 2010, when pandemic H1N1 influenza A circulated, and 850 (51%) patients from November 1, 2010, through April 30, 2011, when seasonal influenza A and B viruses as well as pandemic H1N1 influenza A circulated. The study population comprised 624 (38%) children < 18 years, 783 (47%) adults 18–49 years, and 250 (15%) adults ≥ 50 years of age (Table 1). Slightly more than half of the study population was female, had public insurance, and had no high-risk medical conditions. The study population was 53% black or African American, 34% non-Hispanic white, and 12% Hispanic; 14% were hospitalized. Overall, 14% of enrolled patients in the ED had culture/PCR-confirmed influenza. A higher proportion of patients with than without culture/PCR-confirmed influenza were enrolled in 2010/2011, were 2 to 29 years of age, had no high-risk medical conditions, and were not hospitalized. Among all ED patients with culture/PCR-confirmed influenza, 6% were hospitalized, and 37% presented within 2 days of symptom onset (Table 1). In both 2009/2010 and 2010/2011, a higher proportion of patients with than without rapid influenza tests ordered by their emergency physicians had culture/PCR-confirmed influenza (Table 2). Similar patterns were observed for patients receiving diagnoses of influenza or an antiviral prescription, all of which were oseltamivir, prior to ED discharge. Among all patients who were or were not prescribed antibiotics in the ED, 6% had culture/PCR-confirmed influenza in 2009/2010. In contrast, a lower proportion of patients prescribed antibiotics had culture/PCR-confirmed influenza than those not prescribed antibiotics in 2010/2011. Among the entire study population, a higher proportion of patients with than without rapid influenza tests ordered by their treating emergency physician had high-risk medical conditions in 2009/2010 but not in 2010/2011 (Table 3). Similarly, a higher proportion of patients who were prescribed antiviral therapy had high-risk medical conditions than those not prescribed antiviral therapy in 2009/2010, but not in 2010/2011. There were no significant differences between patients with and without high-risk medical conditions and physician diagnoses of influenza or antibiotic prescribing in either year. Among patients with culture/PCR-confirmed influenza, a higher proportion was diagnosed with influenza and received antiviral prescriptions during their ED visits in 2009/2010 than 2010/2011 (Table 4). In multivariate logistic regression analyses, several factors independently predicted each of three outcomes from the treating emergency physician: rapid influenza test being ordered, diagnosis of influenza, and receipt of antiviral prescriptions (Table 5). The odds of having a rapid influenza test ordered, being diagnosed with influenza, and receiving an antiviral prescription during the ED visits were about fourfold higher for patients with than without culture/PCR-confirmed influenza (adjusted odds ratios of 4.2, 3.9, and 4.2, respectively) while accounting for all other covariates in the model. Patients were more likely to have rapid influenza tests ordered if they were enrolled in 2010/2011, were adults, had no insurance as compared to public insurance, or were hospitalized. Patients were more likely to be discharged with treating physician diagnoses of influenza if they were enrolled in 2009/2010 or had rapid influenza tests ordered. Patients were more likely to receive antiviral prescriptions if they were enrolled in 2009/2010, were female, had rapid influenza tests ordered, had high-risk medical conditions, had symptoms for at ≤2 days, and did not receive antibiotics. An understanding of patterns of rapid influenza test ordering, diagnosis of influenza, and antiviral prescribing by ED physicians could inform programs to enhance influenza epidemic control. The finding that patients with culture/PCR-confirmed influenza had fourfold higher odds of having a rapid test ordered, being diagnosed with influenza, and receiving antiviral prescriptions during their ED visits shows that ED physicians play an important role in successfully identifying patients with influenza. This study found that the likelihood of being diagnosed with influenza or receiving an antiviral prescription were higher in 2009/2010 than in 2010/2011, and this trend toward decreased influenza diagnosis and treatment is important. Rapid influenza diagnostic tests were more commonly ordered in 2010/2011 than 2009/2010, which was anticipated given the recommendations and publications demonstrating poor test characteristics of rapid influenza tests in 2009/2010.21, 46 We found no difference in ordering of rapid influenza tests for patients with symptoms ≤2 or >2 days, although it is possible this result was affected by these 2009/2010 pandemic recommendations. Despite fewer rapid influenza tests being ordered in 2009/2010, almost one-third of patients with culture/PCR-confirmed H1N1 pandemic influenza were diagnosed with influenza and prescribed antiviral therapy during the ED visit. Given that Baxter58 and Keramarou et al.59 demonstrated an association between intense media attention and increased health care use during this 2009/2010 H1N1 pandemic, this finding likely reflected widespread media attention, heightened awareness by the public and medical professions, and specific treatment recommendations.46 Further, we found that patients who had rapid influenza tests ordered during their ED visits were more likely to be diagnosed with influenza and receive antiviral prescriptions. The odds of a child having a rapid influenza test ordered were lower than that for adults, even though rapid influenza tests have been shown to have better performance characteristics in young children than adults.60 Antiviral prescriptions among patients with culture/PCR-confirmed influenza decreased significantly, from 33% in 2009/2010 to 13.5% in 2010/2011, a finding that may reflect the widespread media attention and highly publicized treatment recommendations for the 2009/2010 season.46 The multivariate analysis identified seven independent predictors of patients receiving antiviral prescriptions from their treating physicians in the ED, consistent with the perception that antiviral prescribing among emergency physicians is a complex decision dependent on multiple considerations. Our results are consistent with those of prior studies. Garg et al.26 found that antiviral treatments for influenza are underused and were less common among hospitalized patients with positive physician-ordered influenza tests in 2010/2011 compared to the 2009 pandemic. Mueller et al.25 reported that ED clinicians in 2006/2007 in nine states reported that they were more likely to treat patients who presented within 2 days of illness onset and who had positive rapid influenza tests. Rothberg et al.61 found that physicians, including ED physicians, reported that they did not prescribe influenza antiviral medications for multiple reasons, including presentation too late for treatment, self-limited nature of influenza infection, uncertainty about the diagnosis of influenza, expense of antiviral therapy, limited medication effectiveness, lack of familiarity about antiviral medications, and side effects. Similar to Glezen et al.,56 we found that a higher proportion of patients without than with high-risk medical conditions had influenza. This counterintuitive observation is at least partially explained by higher influenza vaccination coverage among U.S. persons with than without high-risk medical conditions.62 Current clinical practice regarding the diagnosis and treatment of influenza infection in the ED differs from the recommendations from the CDC.63 The CDC recommends antiviral treatment as soon as possible for patients with confirmed or suspected influenza who are hospitalized; have severe, complicated, or progressive illness; or are at higher risk for influenza complications. Persons at higher risk include children younger than 2 years of age; adults ≥ 65 years of age; persons with chronic medical conditions, including asthma, cardiac disease, and epilepsy; pregnant women or women fewer than 2 weeks postpartum or persons with immunosuppression; children on long-term aspirin therapy; persons who are morbidly obese; American Indians and Alaska natives; and residents of chronic care facilities. Oseltamivir was not approved by the FDA for children under 1 year of age in 2010/2011, but was subsequently approved for infants over 2 weeks of age with symptoms for at most 2 days in December 2012.64 These results are from one region in North Carolina and may not reflect those from other geographic locations. Prospective surveillance was performed systematically through daytime work hours from Monday through Thursday, and practice patterns could have differed during evenings or weekends. Although we enrolled a majority of patients who were approached, systematic differences between patients who were and were not enrolled is possible. Additional studies are needed to validate these results. Influenza infection was prevalent among children and adults presenting to the ED during the 2009/2010 and 2010/2011 influenza seasons with fever, acute respiratory symptoms, or both. Patients with culture- or polymerase chain reaction–confirmed influenza were more likely to be diagnosed with influenza and prescribed antiviral medications by their treating physicians in 2009/2010 than in 2010/2011. The ongoing development of molecular diagnostic tests for influenza with increased sensitivity and high specificity, studies that identify practical methods to enhance the diagnosis of influenza and studies that identify patients who are likely to benefit from antiviral treatment are needed to bridge the gap between current practice and Centers for Disease Control and Prevention influenza diagnosis and management recommendations.63 We thank all the patients and their families who participated in this study and all the physicians and staff in the emergency departments at Forsyth Medical Center and Wake Forest Baptist Health who made this study possible. We thank Lauren Vannoy and Shannon Major at Wake Forest Baptist Health; Brian Coleman, James Hobbs, Wendy Hobbs, Eugenia Hutchinson, Brian Miller, Debra Norwood, Keishia Rodriguez, Robert Romanchuk, and Yvonne Whitley at Novant Clinical Research Institute who facilitated the process or enrolled eligible patients; Lauren Vannoy, James Hobbs and Brian Miller who entered data into the database; and Elizabeth Blakeney who performed all the viral cultures and RT-PCR analyses. We also thank the anonymous reviewers whose comments and suggestions significantly enhanced the manuscript.