Influenza prognostication is a tricky business in the best of years and the jury is still out on whether the US will again see low flu activity this season Image by ranasu
Influenza prognostication is a tricky business in the best of years, and the jury is still out on whether the U.S. will again see low flu activity this season. Image by ranasu

Remain vigilant this ‘twindemic’ season

The CDC is anticipating a resumption of seasonal flu activity in the U.S., but the potential effects of the COVID-19 pandemic this year remain unknown.

Reporters often ask infectious diseases physicians like Waleed Javaid, MD, FACP, to foresee the future, whether it's what the SARS-CoV-2 virus will do next or how severe the upcoming influenza season will be.

“I actually have a crystal ball in my office,” he said. He was not joking. “It's a fact—I actually bought it, just because I've needed to answer questions. But it's hard to predict the future.”

Crystal ball or not, prognostication is a tricky business—particularly so a year ago, when experts were attempting to predict what the first combined flu and COVID-19 season in the U.S. might hold. Gregory A. Poland, MD, MACP, director of the Mayo Clinic's Vaccine Research Group in Rochester, Minn., was an early user of the term “twindemic” when expressing concerns for the worst.

But with COVID-19 mitigation measures in place, the U.S. saw unusually low flu activity during the 2020-2021 season. Although final surveillance data are not yet available, model-based estimates from the CDC indicate that flu cases totaled in the thousands rather than the usual millions. It was one of the mildest seasons on record in the U.S., with just one influenza-associated pediatric death reported to the CDC.

“We've never seen this in human history before,” said Dr. Poland, who is also the Mary Lowell Leary Emeritus Professor of Medicine, Infectious Diseases, and Molecular Pharmacology and Experimental Therapeutics at the Mayo Clinic. “If you distance and wear masks, there was [very little] influenza … [or] any of the respiratory diseases that we tend to see,” including respiratory syncytial virus (RSV), parainfluenza, and pertussis.

The flu figures, though they are preliminary, pale in comparison to the previous season's data reported in the U.S. influenza surveillance report. The estimated burden of illness during the 2019-2020 season was moderate, with about 38 million people sick with flu, 18 million visits to a clinician for flu, 400,000 hospitalizations for flu, and 22,000 flu deaths, according to the CDC.

The engine of distribution of the flu virus is thought to be children, who shed more virus for longer periods of time than adults, said infectious diseases physician William Schaffner, MD, MACP, professor of medicine and preventive medicine at Vanderbilt University Medical Center in Nashville, Tenn.

Therefore, he said, perhaps the most important factor in reduced transmission during last year's anomaly of a flu season is that children did not go to school and were sheltering in place rather than sharing the playgrounds. But as the new academic year recently began, people of all ages were again interacting at school, work, and play—some very cautiously and some very freely.

“These will all be opportunities for the [flu] virus to spread. … This summer already, even before school has opened up, there's been an increase in RSV infections and other respiratory infections, particularly in children. And this is not the season for RSV,” Dr. Schaffner said. “So there's a bit of worry that this may be a harbinger of a noteworthy influenza season upcoming. Obviously, we'll have to see. Flu is fickle.”

What to expect?

As Dr. Poland said in the words of his mentor, George Sarosi, MD, MACP, “When you've seen one influenza outbreak, you've seen one influenza outbreak.”

Nonetheless, North American epidemiologists know that in the summertime, the Southern Hemisphere's winter flu season can provide clues as to what to expect. As of August, flu trends in the Southern Hemisphere remained at low post-COVID-19 levels, noted Dr. Javaid, who is professor of medicine and infectious disease and a hospital epidemiologist for Mount Sinai Health System in New York City.

“We are still seeing not as robust of an influenza season as we otherwise would see,” he said. “I think predicting the future here would be that it's likely not going to be as intense as it was before, and the reason for that would be the masking, the social distancing.”

Such COVID-19 mitigation measures appeared to be key factors behind last year's quiet flu season in the U.S., said Dr. Schaffner. “What was clearly very important is that we were locked down, wearing masks, social distancing, avoiding groups, working from home—rather than interacting,” he said. “All these interventions to prevent COVID had an even more profound effect on influenza prevention.”

This upcoming influenza season, the CDC is anticipating a resumption of seasonal flu activity, given the resumption of the spread of other respiratory viruses, said ACP Member Lisa Grohskopf, MD, MPH, medical officer for the influenza division of the CDC's National Center for Immunization and Respiratory Diseases. RSV activity has been on the rise since this past April, and the spread of common human coronaviruses, parainfluenza viruses, and respiratory adenoviruses has been increasing since January or February 2021, according to a July 23 report in MMWR.

Several factors could make this influenza season more severe, including potential increased susceptibility to the virus due to less exposure last season, she noted. “Because there was little influenza virus activity last season, adult immunity (especially among those who were not vaccinated last season) will now partly depend on exposure to viruses two or more seasons earlier,” said Dr. Grohskopf.

Young children also will have lower immunity to influenza, she noted. “They may not have been previously vaccinated or had natural exposure,” Dr. Grohskopf said. “As children return to school and potentially get infected, there could be a higher number of children with no prior exposure to influenza and therefore lower immunity, which could increase illnesses.”

But in a scenario where COVID-19 remains at relatively high levels, driving public health interventions, “I believe we will see less flu this coming season compared to the moderate 2019-2020 season,” said infectious diseases physician Leonard A. Mermel, DO, ScM, professor of medicine at the Warren Alpert Medical School of Brown University and medical director of the department of epidemiology and infection control at Lifespan Hospital System in Providence, R.I.

However, he noted that the timing of flu season could also be affected if COVID-19 cases return to lower levels. Depending on the timing, drops in COVID-19 rates and public health measures could lead to a flu offseason, such as in the spring, he said.

Even if COVID-19 control measures are able to stave off the flu again this year, it remains unknown how well our immunity will work against it in future seasons, added Dr. Javaid. “If we have years of low flu season, would that mean the third year, our immune system has completely forgotten it, and it might go really in the wrong direction?” he said. “[Or] would that mean that the vaccine still would do what it's supposed to do? We do not know that.”

While these concerns have been much discussed, Dr. Schaffner remained more resigned than worried. “All I can say is that the flu will do what it will do, and we'll be responsive,” he said. “I'm hesitant to predict. I think most of us, when it comes to predicting what flu will do, are looking into very cloudy crystal balls. We try to be proactive with the vaccines, but we're reactive to what flu does to us.”

Flu vaccination and testing

Another factor that could exacerbate a potentially severe flu season would be a reduction in flu vaccine coverage. Strong vaccination rates were another highlight of last season: 193.8 million doses of flu vaccine were distributed by late February 2021, a record-high number for the U.S. in a single flu season, according to the CDC.

“It is especially important to be vaccinated against influenza this season,” said Dr. Grohskopf. “Health care providers' strong flu vaccine recommendation is one of the most important factors in patients accepting the vaccine.”

Every year, the recommendations are simple: People older than 6 months of age should get an annual flu shot. “It's true that the flu vaccine is not as effective as COVID vaccine, but as we say each and every year, it helps” by lowering the risks of hospitalization, ICU admission, and death from the flu, said Dr. Schaffner.

“To my patients who would [report], ‘Gee, Dr. Schaffner, you gave me the flu shot, but I still got the flu,’ I would say, ‘Charlie, I'm so glad you're here to complain,’” he said.

This year, all the available influenza vaccines will be quadrivalent, protecting against two A strains and two B strains, said Dr. Schaffner. “It's all quad this year—that's good, we like that—but that brings us to the notion that we actually have to move influenza vaccine into arms,” he said. “There are many of us who are very concerned that there may be not just COVID fatigue out there in the population, but vaccine fatigue.”

Therefore, generating interest in and acceptance of the flu vaccine this fall and winter will be a challenge, Dr. Schaffner said. “Apropos of our membership in the ACP, I hope that every internist is out there virtually requiring, insisting on influenza vaccine for all of their patients,” he said.

Although flu most often peaks in February, clinicians can and should vaccinate beyond Thanksgiving, Dr. Schaffner noted. “I know that internists like to get the flu vaccination season over as quickly as possible, but they will have patients who come in to their offices after Thanksgiving still unvaccinated, and it's still time to give the flu vaccine,” he said.

And internists should be aware that they can administer the flu and COVID-19 vaccines simultaneously, said Dr. Grohskopf. “Vaccines that are given at the same time should be administered at separate sites, separated by more than an inch, if possible.” (Current CDC guidance on coadministration of COVID-19 vaccines with other vaccines is available.)

Some influenza vaccines, like high-dose and adjuvanted ones designed to promote a stronger immune response in older adults, might be more likely to cause some injection-site side effects than other flu vaccines, Dr. Grohskopf noted. “These vaccines can still be given at the same time as COVID-19 vaccines, but in these instances, it's recommended that the influenza and COVID-19 vaccines be given in separate limbs, if possible,” she said.

Getting patients to trust and accept the flu and COVID-19 vaccines can be challenging, but internists can do so like no one else, said Dr. Javaid, who recommended telling hesitant patients you have vaccinated your own loved ones. “When your patients trust you and see that you are trusting the vaccine with yourself and your family, that makes a huge difference.”

One final consideration for internists this season will be patients who present with flu-like symptoms. While it is still difficult to distinguish COVID-19 from flu and other respiratory viruses based on symptoms other than anosmia and dysgeusia, testing capacity is better now compared to last flu season, Dr. Mermel said.

“Testing will be important for those patients who are most likely to benefit from therapeutic intervention,” he said. “Testing is also important for public health reporting so they can keep their fingers on the pulse of local, regional, and national epidemiology of respiratory viruses circulating throughout the year.”

Dr. Schaffner agreed. “I think we as a medical community are going to be doing much more testing this fall than we have because there are reasons to test,” he said. “If you are in a high-risk group and you've just tested positive for COVID, you need monoclonal antibody treatment. If you've got flu, we have antivirals.”

In a patient with overlapping flu and COVID-19 symptoms, test for both viruses, regardless of vaccination status, said Dr. Javaid. “And if you have a respiratory viral panel, it might be not unreasonable to do that, especially in early cases.” (Testing algorithms are available from the CDC.)

Dr. Schaffner also encouraged use of multiplex polymerase chain reaction-based assays to test for respiratory viruses, despite their high cost. “I hope widespread use, as is usual, begins to drive costs down because in many circumstances, multiplex testing is of sufficient cost that it gives doctors pause before ordering it,” he said. “We need cheap, accurate, and quick results from testing, and we're going to need that increasingly for respiratory viruses—not just the different kinds of flu and COVID, but also RSV.”

There may be no crystal ball to predict the future, but there are a few practical ways to control what happens next. Internists seeing patients with flu-like symptoms should keep in mind that office visits are an opportunity for transmission. Patients at U.S. primary care practices with appointments that exposed them to flu-like illness were more likely to return with a similar illness within two weeks compared with nonexposed patients seen earlier in the day, a study in the August Health Affairs found.

While telemedicine certainly has a role in care and can reduce in-office transmission, clinicians will likely need to examine patients with respiratory illness in person and obtain a swab, Dr. Poland said. This can be done safely with appropriate policies in place, including but not limited to vaccine requirements for staff, he said.

“Internists tend not to do this, pediatricians do: Have a sick room and a nonsick room for waiting patients, or stagger out appointments such that you're not exposing people to people you have a high index of suspicion for a febrile respiratory disease,” Dr. Poland said. “And ideally, everybody's wearing a mask—properly.”