Viral infections causing influenza-like illness (ILI) can result in overlapping symptomology that makes accurate diagnoses challenging if based on clinical presentation alone. For more definitive diagnoses of patients with ILI, clinical diagnostic testing must be undertaken, and molecular diagnostic assays offer an ideal combination of accuracy, sensitivity, and speed for achieving this purpose.
Without clinical testing, patients with symptoms of fever of 100°F/37.8°C or higher and a cough and/or sore throat without a known cause other than influenza may be preliminarily diagnosed with ILI.1 Common viruses known to cause ILI include adenovirus (AdV), influenza (flu), human metapneumovirus (hMPV), parainfluenza virus (PIV), respiratory syncytial virus (RSV), and rhinovirus (RV).
Of the three types of influenza that infect humans, only types A and B cause pandemics2 and therefore require readily available diagnostic tests. Although all four types of PIV (1-4) commonly infect children, PIV can cause ILI in adults as well.3 Infections by the different PIV types may vary in clinical and epidemiological features,3 and testing for each type is recommended.
Benefits of molecular diagnostics
An accurate and rapid diagnosis of the agent responsible for a given case of ILI is crucial for directing appropriate treatment of patients and executing precautions to prevent the spread of infection. Turnaround time for laboratory tests is, therefore, a vital consideration when choosing tests to support clinical decision making regarding patients with ILI. Diagnostic capabilities have evolved in recent years. In vitro molecular diagnostic tests, particularly automated tests, provide results more rapidly than traditional culture methods, typically within hours of a sample being extracted, rather than days to weeks.
Although rapid influenza diagnostic tests provide results in approximately 15 minutes, these immunoassays have limited sensitivity compared with molecular or culture-based tests; therefore, a negative result does not exclude actual influenza infection in patients with ILI, particularly when community prevalence of influenza is high.4
Additional benefits of timely and correct diagnoses of the causal ILI virus include decreased total costs of care, reduced inappropriate use of antibiotics which might lead to antimicrobial resistance, and surveillance of circulating viruses for public health authorities.5
Considerations for choosing viral tests
Laboratories in various settings now have access to a broad array of options when selecting molecular tests for respiratory viruses. Some broad-based panels contain tests for 20 or more pathogens, whereas other manufacturers offer individual tests for each agent or small panels with two or three analytes.
Unless justified by clinical need (e.g., immunocompromised patients), testing with a comprehensive panel of ILI-causing viruses may not be cost-effective. For reimbursement purposes, only testing for the most likely agents may be deemed medically necessary, and laboratories that employ only large, multiplexed panels may incur costs associated with running tests for which they receive no reimbursement.
The likely suspects for causal virus may be narrowed through considerations of epidemiology, patient characteristics, and clinical data. For example, although AdV and RV circulate all year, flu, hMPV, PIV, and RSV have a winter seasonal peak.6 During known outbreaks or peak season, diagnostic tests can be chosen to reflect the potential etiologies.
Immunocompromised patients, plus the very young or old, are more likely to host RSV infections than patients without these characteristics,7 which can be confirmed with testing. In addition, AdV, flu, hMPV, PIV, RSV, and RV impose significant risks of morbidity and mortality on immunocompromised and immunosuppressed patients,5 which may warrant molecular testing if such infections are suspected in this subset of patients.
Clinicians may be able to take other factors into account, such as specific symptoms (e.g., bronchiolitis, which usually results from RSV) or repeated presentation of similar cases during a seeming outbreak, to choose the most likely viral cause of a patient’s ILI for subsequent confirmation by molecular testing.
Although molecular assays are designed to detect highly conserved targets in the viral genome, mutations in these regions have developed that affect the sensitivities of some assays, such as assays for the flu itself.8,9 Thus, the introduction of higher-sensitivity assays designed to alleviate issues associated with mutation detection would be of great utility for clinicians and laboratory managers.
The value of flexibility
Based on clinical and epidemiological data, a physician may select specific diagnostic tests for an individual patient with ILI. Cost considerations may limit the choice of tests to those that are medically necessary. Laboratories would, therefore, be well advised to consider flexibility in choice of assays to save money and time by reducing the number of results to review.
In addition, the need for prompt results from these tests to achieve maximum clinical benefit suggests the use of automated molecular diagnostic tests, which generally are available as assays for multiple viruses or viral types. Platforms with multiple assay choices and well-grouped assay analytes, such as by season, provide physicians and laboratory managers with added value beyond speed. The flexibility regarding which assays to use, therefore, is a valuable component of the choice of diagnostic panel as well as the automated platform. As definitive diagnoses become more common and dictated by guidelines, the benefit could also extend to the broader healthcare system, including public health surveillance.
REFERENCES
1. CDC. Overview of influenza surveillance in the U.S.
2. CDC. Types of influenza viruses.
3. CDC. Human parainfluenza viruses (HPIVs).
4. CDC. Rapid influenza diagnostic tests.
5. Juretschko S. Confronting the challenges of influenza-like illness. MLO. 2017;49(11):8-14.
6. Fowlkes A, Giorgi A, Erdman DJ, et al. Viruses associated with acute respiratory infections and influenza-like illness among outpatients from the Influenza Incidence Surveillance Project, 2010-2011. Infect Dis. 2014;209(11):1715-1725.
7. CDC. Respiratory syncytial virus infection.
8. Stellrecht, KA. The drift in molecular testing for influenza: mutations affecting assay performance. J Clin Microbiol. 2018:56(3). pii: e01531-17.
9. Stellrecht, KA. Incidence of matrix genes mutations affecting PCR tests among influenza H3N2 clades circulating during the 2014/15 season. Diagn Microbiol Infect Dis. 2018;91(3):239-244.
