Improving Delivery of Early Treatment to Influenza-Infected Patients

(See the Major Article by Stewart et al on pages 1035–41.) Influenza antivirals consistently reduce morbidity, mortality, and complications when started early across a wide spectrum of clinical illness [1–4]. Despite this fact, there is strong evidence that patients delay presenting for care when they have influenza and that treatment of patients who do present for care falls far short of the ideal. Furthermore, data suggest that patients with laboratory-confirmed influenza are more likely to receive antibacterial therapy, which is likely not needed in most, than antiviral therapy [5, 6]. In this issue of Clinical Infectious Diseases, researchers from the Centers for Disease Control and Prevention and the US Influenza Vaccine Effectiveness (Flu VE) Network publish one of the most significant reports demonstrating the low rate of treatment of influenza-infected patients at high risk of influenza complications [7]. The team analyzed antiviral prescription and clinical data for high-risk outpatients aged ≥6 months with an acute respiratory illness (ARI) and enrolled in the Flu VE Network during the 2011–2012 through 2015–2016 influenza seasons. Additional clinical information was collected from interviews and electronic medical records, and all enrolled individuals were tested for influenza with real-time reverse-transcription polymerase chain reaction (rRT-PCR). From this cohort of 15972 high-risk outpatients, less than half (40%) presented for care early, within 48 hours of symptom onset. Of those who present early for care, only 15% (718/4861) were prescribed an antiviral medication, with a higher rate of treatment (37% [472/1292]) among those with rRT-PCR–confirmed influenza. Earlier presentation to care (odds ratio [OR], 4.1; 95% confidence interval [CI], 3.5–4.8), presence of fever (OR, 3.2; 95% CI, 2.7–3.8), and a positive influenza test result (OR, 4.4; 95% CI, 3.8–5.1) were associated with higher odds of receiving antiviral treatment. The study also found that 25% of high-risk outpatients with influenza were afebrile, consistent with prior studies that suggest fever may be short lived or absent in the elderly, the immunocompromised, and other high-risk patients. Although most of the findings of the study are not novel, the longitudinal nature of the data is. Looking at the overall trend presented in the data, while there was improvement in treatment over the first 3 seasons of the study, the last 2 seasons demonstrated a decline in treatment, particularly in influenza-infected high-risk patients who presented early. This is very troubling in context with the unacceptably low rate of early treatment. While not shown in the current data, prior studies have clearly demonstrated that these same patients typically receive antibacterial therapy at double the rate of antivirals (30% vs 15%) [8]. Because things are not getting better over a 5-year period, and may in fact be getting worse, it is time to look carefully at the problem and develop a different approach to optimized therapy in influenza-infected patients. The clear end goal is to increase the proportion of influenza-infected patients treated with antivirals in a timely fashion while minimizing the exposure to unnecessary antibiotics. To achieve this goal, additional research, expanded use of sensitive diagnostics, and optimized implementation are required. Research is needed to understand the drivers for influenza-infected patients seeking care and their ability to access the care in a timely fashion. From the presented data, only 40% of high-risk patients presented to the physician’s office within 48 hours of symptom onset. From the data, it is unclear if the subjects who presented >48 hours after symptom onset attempted to access care (ie, called for advice), attempted other over-the-counter therapies before seeking care, or did not attempt to seek care until late. One prior study demonstrated that patients with chronic obstructive pulmonary disease or heart conditions were more likely to seek early care whereas those who were unemployed, unable to work, lacked insurance, or who had diabetes or kidney disease were less likely to seek early care [9]. Understanding the drivers to the delay will help to encourage patients to seek care earlier and may help to address social, medical, and economic barriers to care. Further studies may identify systems gaps inhibiting timely care. Clinics need to have the capacity and flexibility to see an influx of patients when respiratory viruses circulate. Lack of capacity may result in approaches to reduce patient visits and attempt to manage patients expectantly. The second key research object is to understand how clinicians approach patients with acute respiratory infections and how they decided to prescribe antivirals, antibacterials, or symptomatic management. There has been significant effort placed on minimizing antibiotic use for respiratory viral infections, yet the data continue to document overprescribing of antibiotics. In addition to speeding recovery of the clinical illness, the neuraminidases have been demonstrated to reduce the need for antibiotic-requiring complications, adding further data to support use of the antivirals, particularly in high-risk patients [10, 11]. Understanding concerns clinicians have about antivirals and what information they need to be comfortable to prescribe antivirals will allow the development of clearer messages to optimize therapy for influenza-infected patients. Newer diagnostics, including digital immunoassays (DIA) that utilize automated immunochromatographic antigen detection and rapid nucleic acid amplification tests (NAATs), are increasingly available. Both DIAs and rapid NAATs are ideal for point-of-care testing as they are Clinical Laboratory Improvement Amendments waived, and have fast turnaround times (5–30 minutes) and sensitivity that approaches that of traditional RT-PCR assays [12]. Some of the assays allow for simultaneous detection of influenza and respiratory syncytial virus infection [13]. Across the range of clinical severity, patients who test positive for influenza are more likely to receive early therapy. This fact was confirmed in the current study, which demonstrated a 4.4-fold higher odds of patients getting treatment if they had a positive confirmatory test for influenza. Current guidance recommends that antivirals should be given to high-risk individuals with clinically suspected influenza, with testing deferred when influenza is known to be circulating in the community; clinical practice falls far short of the guidelines, as demonstrated in this study. Given the realities that clinicians want a diagnosis to treat influenza and newer assays have markedly improved sensitivity, efforts should be made to expand the availability and use of these assays. Guidelines, too, should be brought in line with these realities and should encourage testing if it will increase the appropriate use of antivirals. This will become even more important as the armamentarium of antivirals for other respiratory viruses expands and selecting the right antiviral will be even more important. Enhanced availability and use of such assays likely will drive more appropriate, early use of antivirals and should decrease unnecessary antibacterial therapy and therefore improve patient outcomes. Implementation research is also needed to enhance the use of diagnostic tests and using the results to optimize antiviral and antibacterial prescribing. Implementation science will inform barriers to and methods of promoting the systematic application of the research findings outlined above—particularly important as there are true challenges to making these newer agents available at a range of sites to facilitate a timely diagnosis, including costs, logistics, and regulation. This is especially important, given the impact of reclassification of rapid influenza antigen assays effective 12 January 2018 by the US Food and Drug Administration (Federal Register Document 82 FR 3609, pages 3609–19), which affects some of the most commonly utilized assays clinically. With this study and several other related studies across a range of clinical settings, there is the consistent finding of suboptimal antiviral prescribing that is not improving and may, in fact, be getting worse. As such, it is critical that funding agencies and foundations support the research to outline a path forward and then implement solutions based on the findings to improve the care of influenza-infected patients. Documenting the poor performance alone does not move the field forward. In the end, it is time for clinicians to stop ignoring influenza and to consistently prescribe the antivirals that will speed recovery from influenza, reduce influenza-associated complications, and reduce the prescribing of unnecessary antibiotics. Potential conflicts of interest. The author has received grants from Beckman Coulter, Cepheid, Chimerix, Gilead, Janssen, and Shire; personal fees from Celltrion, Chimerix, Farmark, Genentech/Roche, Toyama/MediVectro, Seqirus, and Shionogi; and is a paid member of a Data and Safety Monitoring Board from Shionogi and GlaxoSmithKline. The author has submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.