Influenza testing has changed significantly in the last 10 years. New options have taken us from culture to the use of molecular detection. Whether it's point-of-care testing or molecular testing, there is a new understanding about the strengths and weaknesses of the various technologies. It's important to have a thorough understanding of the use of these methods and the environments in which they are most appropriate. It's also important to understand the costs associated with testing, whether it’s a financial cost to the patient, or a medical cost (getting the results in time to make treatment decisions). Also included is a discussion of the steps that laboratories should take to come to a decision on which testing to offer.
Presenter and Credentials:
Thomas Grys, Ph.D., Assistant Professor of Laboratory Medicine and Pathology
Consultant in Laboratory Medicine and Pathology at Mayo Clinic in Arizona.
Welcome to Mayo Medical Laboratories Hot Topics. These presentations provide short discussion of current topics and may be helpful to you in your practice.Introduction
Our speaker for this program is Dr. Thomas Grys, an assistant professor of Laboratory Medicine and Pathology and a consultant in Laboratory Medicine and Pathology at Mayo Clinic in Arizona. Dr. Grys discusses the latest information about influenza including the 2016-2017 vaccinations, the testing available for detection, and the strengths and weaknesses of that testing. Dr. Grys, thank you for presenting with us today.
Thank you for that introduction.
I have no disclosures relevant for this topic.
Today we will be discussing updates of influenza for the 2016-2017 season including vaccinations, influenza diagnostic tools, and implementation of testing methods.
Influenza is an RNA virus. Unlike most bacteria, viruses are unique in that their replication and survival depends on the host cell machinery for replication. Transmission occurs primarily through droplets. This can be through inhalation of droplets from another’s cough or sneeze, or by direct inoculation. That is to say, when droplets or secretions are present on a surface, a person may touch that surface and then touch their eyes, nose, or mouth and directly place the virus-containing secretions into their own mucous membranes. Influenza causes yearly epidemics. Symptoms are nonspecific and mimic those experienced during infection with other respiratory diseases. Commonly, infections cause fever, muscle aches, headache, fatigue, cough, and sore throat. Although the intensity and severity of disease varies from year to year, the overall average number of hospitalizations is over 200,000 per year, and the deaths attributable to influenza average 36,000 per year in the United States. Antiviral medications are available, but the reduction of symptoms for a routine infection is modest. The drugs can be expensive, and the effectiveness is reduced as time from symptom onset increases. This last issue, time from symptom onset to treatment, has a direct impact on testing. More to come on this later in the talk. For a clear, concise, and complete discussion of influenza biology, please refer to the 2015 Hot Topic Influenza Update by Dr. Matthew Binnicker.
Vaccines for 2016-2017
The World Health Organization has a group that reviews data such as epidemiology of influenza strains, severity of disease, and other data to make recommendations for what strains to include in each season’s vaccine. In the United States, the Food and Drug Administration, or FDA, chooses the final composition of vaccines each year and approves products from vaccine manufacturers. For the 2016-2017 season, there are 2 types of vaccines approved either with 3 or 4 strains. All vaccines in the United States have 2 strains of influenza A and at least 1 strain of influenza B. New products for this season include 2 that are designed to produce a more protective immune response in people 65 years and older. One is a higher dose of a typical vaccine composition, while the other includes an adjuvant, a non-virus ingredient that boosts the immune response. Most vaccines are produced in eggs, but there is also one produced in cell culture.
Vaccination Updates for 2016-2017
Advisory Committee on Immunization Practices, or ACIP, is a group of experts in the United States who are appointed by the Secretary of the US Department of Health and Human Services. Their charge is to decide how to use vaccines to address diseases based on epidemiology of disease, availability of vaccines, etc. In addition to decisions for vaccines for childhood immunizations, they also make recommendations each year for influenza. For 2016 and 2017, ACIP does not recommend the use of the nasal spray vaccine, the live attenuated influenza vaccine. Other updates for this season relate to people who have egg allergies. For those people who only have mild allergies, that is to say hives, any licensed vaccine may be used. For those with more severe reactions to egg, any licensed vaccine may also be used; however, it is suggested that they be given in a medical setting with healthcare supervision that can recognize and manage any allergic reaction that may result. Since most reactions tend to be fairly immediate, the ACIP no longer recommends a 30-minute wait time after the vaccination.
Traditional Methods of Detection
For decades, viral culture was the mainstay and the default reference standard for detection of influenza. In the context of today’s technologies, culture provides a fairly sensitive but slow time to result. For the laboratory, culture requires a high level of space and effort. A benefit to culture is the ability to generate viral isolates, which is essential for public health efforts. Two benefits to introduction of rapid antigen testing is the short time to result and the ability to do testing outside of the microbiology laboratory. For the patient, there is a quick answer, but we now know that these tests vary widely in sensitivity and specificity. For the laboratory, the impact varies. When performed as point-of-care, there is a lower demand on lab resources. When performed in the lab, this single-use, single-throughput type of testing can take more time than a batch type of test. Complicating matters for the evaluation of performance is the fact that prevalence of disease affects performance characteristics. Positive results in a low prevalence setting make it more likely that the result may be falsely positive, for instance, in summer when influenza is very low. Negative results during high prevalence is more likely to be false-negative when the rates of disease are high such as February, when influenza tends to peak. In summary, the overall performance of the rapid antigen test is moderate to poor. Negative results must be confirmed by alternative methods to avoid missing a true-positive. These tests should be used in communication with the microbiology laboratory to be sure they are used at the right time of year, in the right patient population, and to be sure that necessary alternative testing is available.
Molecular Detection: Nucleic Acid Amplification Tests
Molecular testing generally describes nucleic acid testing, or NAT, technology such as PCR where nucleic acid targets are amplified. This allows for high sensitivity and high specificity. The technology has blossomed from a single target test to syndromic testing and now to rapid point-of-care testing. I do not intend for these paradigms to be a progression where one is better than the other. Rather, they are 3 different approaches to testing, each with benefits and drawbacks, and each can be relevant in particular situations.
Paradigm 1: Single Analyte Tests
Paradigm 1 includes single analyte tests where we are detecting just influenza A or influenza A and B together. Examples of this first were laboratory-developed tests where the laboratory would put together its own test to target influenza. There are now FDA-cleared assays that target just influenza A and B. The impact on the laboratory is that the laboratory had to acquire new instruments, sometimes expensive, and learn new methods and learn new skills in the laboratory such as pipetting small volumes and being aware of molecular contamination so as not to contaminate primary specimens with influenza virus. These are a higher cost to perform for the reagents and instruments than viral culture, and they can be higher effort and often are batched for these reasons. The impact to the patient is that they are a higher sensitivity and specificity; however, that comes with a higher charge to the patient. There is a longer time to result than rapid antigen tests because these single analyte tests typically are performed in the laboratory versus as a point-of-care. The care decisions, however, are made on reliable information as the performance of these tests tends to be very good.
Paradigm 2: Syndromic Testing
The next paradigm we will discuss is syndromic testing. The strategy to syndromic testing is that many of these respiratory diseases present in a similar way and cannot be differentiated based on particular symptoms, so why not test for several pathogens or many that can cause those symptoms, all at the same time. Examples of this are small panels of influenza A, B, and RSV or larger that can detect up to 20 pathogens including some nonvirus targets. The impact on the laboratory is again often the requirement of new instruments; however, sometimes this means a lower complexity test than a laboratory-developed test because many of these are performed in a cartridge-based format with minimal processing steps. One particular twist to performing these in the laboratory is that it has brought new challenges for quality control and also the logistics of how to order and report these and, overall, these tend to be a high cost to perform in the laboratory. The impact to the patient is that these can be a high or very high charge to the patient. Often these results come out faster from the laboratory than a single analyte test. However, some of the analytes tested for may not change the care for the patient if they are an outpatient, so typically these are reserved for inpatients or other complex patient populations.
Paradigm 3: Point of Care
Paradigm 3 is point-of-care molecular testing. There are now several FDA-cleared assays, which can provide results in 30 minutes or less. Some of these have waived status and can be performed outside of the laboratory. The impact on the laboratory is that they can be a high effort if performed in the lab because again they are often a 1 specimen, 1 test workflow, which does not provide economies of scale for the effort as happens in batch testing. When these tests are performed outside of the laboratory in a point-of-care environment, there is some loss of control for the laboratory for who is performing it, how quality control is performed, and the other logistics of lab testing. Some of the issues that must be addressed if these are brought in include who in the laboratory gets the revenue, whether it be the performing providing service or the laboratory, how to report these, how to document these. This is emerging in a time with electronic medical records, so interfaces become important and sometimes complicated. The impact to the patient can be very helpful because oftentimes a care decision can be made before the patient leaves the premises. This may be one of the best tools for antimicrobial stewardship because if a positive result is found for influenza, then the patient can avoid taking an antimicrobial drug that is not indicated. However, sometimes overtesting occurs. If the test result from a rapid influenza test is not going to be used to change patient care, it may not be indicated. For instance, antivirals can be expensive, and often the patients may not want to pay for them, so producing a test result may not result in the patient actually taking the drug. If that is the situation, then the provider may choose to not test, and many hospitals have their own algorithms for when testing is indicated and when it is not. Also, even when influenza is found by one of these tests, there may be extenuating factors that still require additional treatment, for instance, if there is a possibility for a secondary bacterial infection. So, often, additional microbiologic testing or other lab testing may be indicated whether or not influenza testing is performed.
Overall, the last 10 to 15 years has seen a Copernican revolution. Culture used to be the common and default gold standard, antigen testing was widespread, and molecular testing was new and unproven. Now, culture is less common, antigen tests are used carefully but often have been replaced entirely by molecular, and now there are a wide variety of molecular options from single analyte testing, syndromic, to point-of-care molecular.
Test Selection: Step 1 Define Current State and Resources
I will now discuss 3 steps in determining what test to select. The first step is to define the current state and resources. It is important to first evaluate the current testing practices and identify any rapid antigen testing that may be occurring in your healthcare system. Often, some doctors’ offices are using these, and the laboratory does not even know. It is important to identify these practices to have a more streamlined and standardized approach. It is important to consider stand-alone influenza testing versus small panels or syndromic panels. Finally, consider space and skills necessary to support the point-of-care and/or rapid testing in the laboratory. If resources are unavailable, it may limit the options you have for testing.
Test Selection: Step 2 Engage the Practice to Support Needs
The next step is to engage the practice and support their needs. Start with the patient and the provider; what decisions are being made, what actions will be taken. If treatment is not indicated, testing may not be needed. Then define the range of opportunity. Perhaps it is important to have a short time to result, or if there are local resources for testing and a postvisit support such as a phone call or given a result through a phone app, then there are other ways to help get the patient the result and get the provider the result to make that healthcare decision. Finally, engage institutional leadership. Influenza testing and treatment recommendations should be followed and reviewed annually as epidemiology changes and antiviral drugs become available. It is important to evaluate opportunities to support the recommendations of national guidance standards as well as within the healthcare system to best support the patient care decisions.
Test Selection: Step 3 Synthesize Needs and Resources
Finally, we evaluate the intersection of the available resources and the opportunities to best impact care decisions. It is important to educate the practice at all levels to help them understand how to place orders, how to perform the method if it is a point-of-care assay, and the expectations on who is doing the quality control, how to document, how to do competencies, and so forth. Communication is vital. So in addition to just an email, it may be important to visit departments or to have information available on internal websites. Finally, evaluate. Track test utilization; try to determine how many of the tests are resulting in the care decisions that are intended. Evaluate the cost to the laboratory, the reimbursement for each test, and any impact on FTE whether performed as a point-of-care or inside the laboratory. These are all important factors and together result in a positive benefit to the healthcare system or perhaps unintended consequences.
In summary, influenza testing is unique. The virus is seasonal, and there are intense increases in volumes during the peak season. Care decisions must be made rapidly for optimal outcome of the patient. Each patient care setting and each year, in fact, brings unique challenges. However, there are a variety of testing and treatment tools now available. Each healthcare system must evaluate their needs and the tools available to best serve the needs of their patients.
Finally, I share these helpful resources: the CDC webpage for influenza and the Hot Topic for influenza from last year from Dr. Binnicker, which has the nice summary of influenza biology.