For the past two years, the United States has experienced milder influenza seasons, thanks to infection prevention measures taken for the COVID-19 pandemic. However, there is concern among the infectious disease community on how the Northern Hemisphere’s upcoming flu season will look since many COVID-19 distancing and masking measures have been relaxed.
To be sure, this is not a new concern. Last summer and fall, public health experts expressed fears of a “twindemic” —the possibility that not one but two major respiratory viruses would wreak havoc on the population. In the following flu season, however, remarkably little influenza activity was seen. Many people still wore masks, distanced socially, washed their hands carefully, and stayed home more often than they did prior to the pandemic.
Per the CDC, reduced population immunity due to lack of flu virus activity since March 2020 could result in an early and possibly severe flu season this year as SARS-CoV-2 continues its widespread circulation in many countries.1 Influenza trends are notoriously difficult to predict, but clinical laboratories must do their best to prepare as they plan their testing strategy and stock up on the kits, consumables, and supplies they expect to need.
With so much uncertainty, most clinical labs will benefit from an approach that offers as much flexibility as possible. Comprehensive molecular tests for all widely circulating respiratory viruses—including influenza A and B, respiratory syncytial virus (RSV), and SARS-CoV-2—will be important for streamlining the testing process, detecting dangerous co-infections, and generating results quickly enough to get patients on the right treatment in a clinically relevant time frame. In addition, testing platforms that offer scalability to manage ebbs and flows in demand will allow labs to prepare for an unpredictable season. Finally, ease-of-use should be prioritized, both to optimize the lab workflow and to accommodate staffing shortages that may occur with surging COVID-19, flu, or RSV cases.
Respiratory virus trends
As lab staff members in the Northern Hemisphere brace themselves for flu season, they typically look to their counterparts in the Southern Hemisphere for indicators of that year’s flu severity. Public health agencies also attempt to broadcast information that may be useful for planning.
This summer, the World Health Organization flagged increasing influenza activity in some areas of the Southern Hemisphere, particularly in temperate zones such as southern Africa, Australia, and New Zealand.2 The organization also warned of great uncertainty in the ability to predict flu activity amid the COVID-19 pandemic: “The current influenza surveillance data should be interpreted with caution,” it reported.
In July this year, when it is Australia’s winter, flu cases surpassed rates seen prior to the pandemic, with weekly case numbers higher than the country’s five-year average.3 In addition to these high rates, the Australian metrics are concerning because flu season, which typically runs from June to September, started in April. Beginning so much earlier than usual could be an indicator of lower-than-average immunity in the population. At the same time, the country is dealing with some of its highest transmission rates of SARS-CoV-2 infection due to the recent emergence of the BA.5 strain.
Because relatively few people have been exposed to flu, RSV, and other common respiratory viruses in the past two and a half years, infectious diseases experts believe population immunity levels may be unusually low.4 Some have warned that when these viruses do resurface, they will run rampant among an unprotected public. Of course, the low level of flu activity in the past two years also means that it is much more challenging for vaccine makers and other researchers to predict which influenza strains will be most common.5 If this year’s vaccines are largely ineffective, that could make a bad flu season even worse.
In North America, respiratory virus trends are already suggesting that the coming flu season may be worse than usual—or, at least, even less predictable. For instance, despite a minimal flu season last winter, cases of influenza surged in the U.S. in May 2022, a time when flu cases are typically in decline. According to the Centers for Disease Control and Prevention, the numbers seen at that time represented “the highest weekly rate observed during that week since the 2010-2011 season.”6The timing of that late-season surge correlates with relaxed or abandoned mask mandates, workers returning to the office, and the elimination of other pandemic mitigation measures.
In addition, the recent activity of other respiratory viruses has also appeared to be unusual. Large outbreaks of RSV, generally associated with winter infections, have occurred in the summer and early fall in Europe and the United States.7 Anecdotal evidence suggests that everything from colds to strep throat and beyond have rebounded as kids returned to schools, often with more severe symptoms than usual. With most of these pathogens out of circulation for the last two years, they are now encountering vulnerable communities with far less built-up immunity.
Comprehensive testing
In an average flu season, clinical laboratories may find it beneficial to adopt targeted respiratory panel tests — often encompassing influenza A, influenza B, and RSV — to generate answers about all the common culprits from a single test. With the pandemic still going strong, this kind of panel-based testing is no longer simply helpful; it is downright critical for patient health.
In a recent study, scientists in the United Kingdom analyzed data from more than 200,000 patients with COVID-19 admitted to hospitals between February 2020 and December 2021.8 Of those, nearly 7,000 patients were tested for other infections, and nearly 600 were found to have influenza, RSV, or an adenovirus. A detailed analysis revealed that patients with COVID-19 and flu had significantly worse outcomes: they were four times as likely to require mechanical ventilation and twice as likely to die compared to patients with just COVID-19.
“As public health restrictions are lifted, respiratory virus co-infections are more likely to occur during future winters,” the study’s authors reported. “Testing for influenza viruses is important in hospital inpatients with COVID-19 to identify patients at risk and a cohort of patients who might have different responses to immunomodulatory and antiviral therapy.”
The call for comprehensive testing goes well beyond that study. The World Health Organization has also urged countries to perform integrated surveillance for both influenza and SARS-CoV-2 and recommended that clinicians should consider influenza as they diagnose patients with respiratory symptoms even outside of the usual flu season.2
Clinical lab testing for multiple respiratory viruses in each patient would be daunting if it weren’t for molecular panel tests. These tests, based on nucleic acid amplification, are designed to seek out the genetic signatures of many different pathogens in a single assay, reporting all results together from one workflow. Molecular assays, which are recommended for flu testing by the Infectious Diseases Society of America, feature better sensitivity compared to rapid antigen tests or conventional fluorescent antibody assays.9,10 They also tend to deliver results quickly, making it possible to get patients on the right treatment in a clinically relevant window.
Of course, there is a risk of over-testing with large panel assays that go well beyond the usual respiratory pathogens. For the upcoming flu season, a targeted panel covering flu A/B, RSV, and SARS-CoV-2 would deliver the comprehensive results needed to triage most patients without being excessive in costs or staff resources. Indeed, many payers prefer targeted panels to larger panels for generally healthy patients, offering a clearer path to reimbursement for the more targeted assays while reserving larger panels for immunocompromised and other highly vulnerable patients.11
Sample-to-answer systems
Another key benefit of molecular assays is that many of them can be run on sample-to-answer platforms or automated systems that handle all processing steps internally and require minimal intervention from the user. Typically, a clinical lab technician will load the patient’s sample into a cartridge or other consumable, place it into the testing instrument (possibly with several other cartridges or consumables at the same time), and press start. At the end of the run, results are available for all pathogens included on the test selected.
Sample-to-answer platforms usually offer low to mid throughput, making them a good fit for all but the highest-throughput laboratories. They deliver results quickly for a handful of samples—generally from 30 minutes to a few hours—and some can accommodate both stat and batch testing. These systems can be useful for labs looking to manage uncertain testing volumes without needing more personnel and still delivering same-day results to physicians.
Conclusion
Attempting to predict something as unpredictable as flu season is challenging in normal times, and virtually impossible amid a pandemic caused by another respiratory virus. But for the clinical laboratory, making these predictions is essential for assembling resources, selecting and validating a testing strategy, and making other key preparations to ensure they can manage the needs of their patient population in the months ahead.
Early indicators suggest that the coming flu season in the Northern Hemisphere may start earlier than usual and be more severe than usual as influenza strains spread through populations that have had little recent exposure or immunity. The pandemic mitigations that have kept the flu at bay for so long—such as masking, social distancing, and spending time at home rather than in the office, school, or other shared spaces—have largely been discontinued, giving influenza the opportunity to spread.
Given those factors, clinical labs should prepare for the possibility of early and significant flu transmission and for cases of respiratory coinfections. Comprehensive molecular testing for the most common respiratory pathogens and the adoption of sample-to-answer platforms to generate rapid results could help labs meet spikes in demand despite ongoing and future staffing shortages.
References
- CDC. Frequently asked influenza (flu) questions: 2021-2022 season. Centers for Disease Control and Prevention. Published May 26, 2022. Accessed August 4, 2022. https://www.cdc.gov/flu/season/faq-flu-season-2021-2022.htm.
- Influenza update N° 422. Who.int. Accessed August 4, 2022. https://www.who.int/publications/m/item/influenza-update-n-422.
- Tate N. Is Australia’s COVID, flu ‘twindemic’ A warning for the U.s.? WebMD. Published July 21, 2022. Accessed August 4, 2022. https://www.webmd.com/cold-and-flu/news/20220721/australia-twindemic-a-warning-for-the-us.
- Hunter P. The return of the seasonal flu and cold: Other diseases are set to rebound as Covid-19 restrictions ease. EMBO Rep. 2022;5;23(4):e54932. doi: 10.15252/embr.202254932. Epub 2022 Mar 10. PMID: 35267239; PMCID: PMC8982594.
- Dhanasekaran V, Sullivan S, Edwards KM, Xie R, Khvorov A, Valkenburg SA, Cowling BJ, Barr IG. Human seasonal influenza under COVID-19 and the potential consequences of influenza lineage elimination. Nat Commun. 2022;31;13(1):1721. doi: 10.1038/s41467-022-29402-5.
- CDC. FluView summary ending on may 14, 2022. Centers for Disease Control and Prevention. Published May 20, 2022. Accessed August 4, 2022. https://www.cdc.gov/flu/weekly/weeklyarchives2021-2022/week19.htm.
- Branswell H. Viruses that were on hiatus during Covid are back — and behaving in unexpected ways. STAT. Published May 25, 2022. Accessed August 4, 2022. https://www.statnews.com/2022/05/25/viruses-that-were-on-hiatus-during-covid-are-back-and-behaving-in-unexpected-ways/.
- Swets MC, Russell CD, Harrison EM, Docherty AB, Lone N, Girvan M, Hardwick HE; ISARIC4C Investigators, Visser LG, Openshaw PJM, Groeneveld GH, Semple MG, Baillie JK. SARS-CoV-2 co-infection with influenza viruses, respiratory syncytial virus, or adenoviruses. Lancet. 2022;16;399(10334):1463-1464. doi: 10.1016/S0140-6736(22)00383-X.
- Miller SA, Deak E, Humphries R. Comparison of the AmpliVue, BD Max System, and illumigene Molecular Assays for Detection of Group B Streptococcus in Antenatal Screening Specimens. J Clin Microbiol. 2015;53(6):1938-41. doi: 10.1128/JCM.00261-15.
- Couturier BA, Weight T, Elmer H, Schlaberg R. Antepartum screening for group B Streptococcus by three FDA-cleared molecular tests and effect of shortened enrichment culture on molecular detection rates. J Clin Microbiol. 2014;52(9):3429-32. doi: 10.1128/JCM.01081-14.
- Ibbotson, S. Paying for molecular diagnostics. CLPMAG. Published May 14, 2019. Accessed August 4, 2022. http://www.clpmag.com/2019/05/paying-molecular-diagnostics/.
