US Pharm. 2022;47(12):43-47.

Why Older People Are More Susceptible to the Flu

Though the COVID-19 pandemic provided a brief respite, influenza virus is back in circulation and, as usual, poses a special danger to people aged older than 65 years. But why are older people more susceptible to the flu? New research from the University of Michigan Medical School, published in Nature Communications, offers clues.

The study, led by first author Judy Chen, a PhD candidate, senior author Daniel Goldstein, MD, the Eliza Maria Mosher Collegiate Professor in Internal Medicine and Professor of Microbiology and Immunology, and their team investigated why cells called alveolar macrophages, the first line of defense in the lungs, appear to be compromised with age.

These macrophages are immune cells that attack invaders like the flu virus and live in the small air sacs, or alveoli, inside the lungs. Importantly, these cells appear to be lost with aging.

Previous research by another group showed that when macrophages from an old mouse were put into a young mouse, the cells looked young again. “This drove us to believe that something in the environment of the lungs is contributing to this,” said Ms. Chen.

Signs pointed to a lipid immune modulator known as prostaglandin E2 (PGE2) with wide-ranging effects, from labor induction in pregnancy to inflammation in arthritis. The study team discovered there is more PGE2 in the lungs with age. This increase in PGE2, she explained, acts on the macrophages in the lung, limiting their overall health and ability to generate.

The team suspects that the buildup of PGE2 is yet another marker of a biological process called senescence, which is often seen with age. Senescence serves as insurance against the runaway division of damaged cells; cells that are senescent are no longer able to replicate. “One of the interesting things about these cells is they secrete a lot of inflammatory factors,” said Ms. Chen.

The study showed that with age, the cells lining the air sacs in the lungs become senescent, and these cells lead to increased production of PGE2 and suppression of the immune response. To test the link between PGE2 and increased susceptibility to influenza, they treated older mice with a drug that blocks a PGE2 receptor. “The old mice that got that drug actually ended up having more alveolar macrophages and had better survival from influenza infection than older mice that did not get the drug,” said Ms. Chen.

The team plans to investigate the various ways PGE2 affects lung macrophages, as well as its potential role in inflammation throughout the body. “As we get older, we become more susceptible not only to influenza but to other infections, cancers, autoimmune diseases as well.”

Smoking Increases Risk of Illness and Viral Infection

A study led by University of California Davis (UC Davis) Comprehensive Cancer Center researchers shows that current smokers have a 12% increased risk of a laboratory-confirmed viral infection and a 48% increased risk of being diagnosed with respiratory illnesses. These results did not vary by type of virus, including a coronavirus.

In combination with past discoveries, the current findings published in Nicotine & Tobacco Research support urgent recommendations to increase tobacco control efforts for countering COVID-19.

“Past research has shown that smoking increases the risk of COVID-19 disease severity, but the risk of infection had been less clear,” said UC Davis tobacco researcher and lead author of the study Melanie Dove. “Our study findings show smokers have an increased risk of viral infection, including a coronavirus and respiratory illness.”

The researchers reanalyzed data from the British Cold Study (BCS), a 1986-1989 challenge study that exposed 399 healthy adults to one of five common cold viruses. This included a type of common coronavirus (coronavirus 229E) that existed prior to the novel coronavirus (SARS-CoV-2), which causes COVID-19 disease. (Data from the BCS are available on the Carnegie Mellon University “The Common Cold Project” website.)

The UC Davis researchers calculated overall and coronavirus-specific unadjusted and adjusted relative risks for current smokers and each outcome (infection and illness), testing whether each association was modified by type of respiratory virus.

The data showed that current smokers had an increased risk of respiratory viral infection and illness, with no significant difference across the types of viruses. The increased associations for only the coronavirus 229E did not reach statistical significance. This was likely due to the small sample size with only 55 participants, of whom 20 were smokers.

These findings are consistent with known harms caused by smoking to immune and respiratory defenses and some observational evidence of increased COVID-19 infection and disease progression in current smokers.

“Besides examining associations by type of virus, a key reason we reanalyzed the original BCS is to report a risk ratio instead of an odds ratio,” Dr. Dove explained. “Odds ratios may overestimate the strength of an association if an event is not rare (>10%), so our results are a little lower (1.48 compared with 2.1 in the BCS). The relative risks from this study can provide an estimate of the strength of associations that can be used to guide tobacco control decisions.”

Compared with other study designs, the BCS is considered a high-quality study because of its randomized trial design, little missing data, clear smoking status definitions, and laboratory-confirmed data. Observational studies have limitations. These include current smokers being more likely to get tested due to increased symptoms and smoking status being underreported in electronic health records. Additionally, infected individuals who stop smoking immediately prior to testing or hospitalization are often recorded as a nonsmoker or former smoker.

One of the main limitations of this study is that the mild common coronavirus 229E may have different biological and health effects than other coronaviruses, including SARS-CoV-2. In other words, the findings may not be generalizable to other coronaviruses.

“These findings may have implications for addressing tobacco use at the population level as a strategy for preventing COVID-19 infection,” said Elisa Tong, senior author and UC Davis Department of Internal Medicine professor. “A quarter of the U.S. population currently smokes or has high levels of cotinine, a nicotine metabolite, and there is no safe level of smoke exposure for nonsmokers. Global tobacco control is urgently important too, as many countries have even higher smoking prevalence rates.”

Researchers Identify Flu-Fighting Pathways

Researchers have identified the gene TDRD7 as a key regulator against influenza A virus (IAV), which causes respiratory tract infections in 5% to 20% of the human population. These findings could facilitate the development of novel therapeutic interventions against influenza virus infection. The study, led by the Icahn School of Medicine at Mount Sinai in collaboration with other institutions, was published in Science Advances.

IAV is responsible for 250,000 to 500,000 deaths per year worldwide. When IAV infects its host, an immunologic response composed of a series of molecular processes begins. IAV can infect several different species, and physiological and genetic differences among these species can contribute to different host responses, although some responses are shared.

“Identifying key defense processes and key regulators in multiple species can facilitate the development of treatments for IAV in humans,” said Bin Zhang, PhD, director of the Center for Transformative Disease Modeling, Willard T.C. Johnson Research Professor of Neurogenetics, and professor of genetics and genomic sciences at Icahn Mount Sinai, who led the study.

The study used RNA sequencing to analyze gene expression over time in cells and tissues collected from IAV-infected humans, ferrets, and mice, identifying multiple key defense processes specific to tissues and species. One gene found to play a key role in immunologic defense mechanisms against IAV across all species was TDRD7, which encodes a Tudor domain–containing protein, a type of protein shown to be involved in epigenetic regulation. In light of this discovery, the researchers conducted subsequent experiments inhibiting the function of TDRD7, resulting in an increase of virus replication in IAV-infected models.

“Identifying both common and species-specific responses to influenza is essential in developing effective therapies for the flu and can help inform future research of other respiratory infections, such as COVID-19,” said Christian Forst, PhD, assistant professor of genetics and genomic sciences, and microbiology, at Icahn Mount Sinai and a first author of the study.

High Prevalence of COVID-19 and Flu Coinfections

Researchers from the University of Missouri School of Medicine have discovered a high prevalence of COVID-19 coinfections in central Missouri during the 2021-2022 flu season, with a monthly coinfection rate as high as 48% among individuals with COVID-19.

The findings come from 462 patients at University of Missouri Health Care who tested positive for COVID-19 and were subsequently tested for influenza. Of those who tested positive for COVID-19, 33% also tested positive for the flu.

“Coinfection in our samples peaked in October 2021 at 48% when the Delta variant was dominant and reached the lowest point at 7.1% in January 2022 when the Omicron variant prevailed,” said senior author Henry Wan, PhD, professor of molecular microbiology and immunology, veterinary pathobiology, electrical engineering, and computer science. Dr. Wan also directs the NextGen Center for Influenza and Emerging Infectious Diseases and is a primary investigator at the Bond Life Sciences Center.

Of the 462 patients infected with COVID-19, 51% had the Delta variant, while 38% had the Omicron variant. Those who were infected with the Omicron variant and those who received at least one influenza vaccine during the 2020-2022 influenza seasons were less likely to become coinfected with both the flu and COVID-19. They were also less likely to become hospitalized.

“Despite low flu vaccine effectiveness for the 2021-2022 season, which was estimated at less than 16%, our study highlights the importance of influenza vaccinations, as they appear to not only offer some protection against influenza infections but, importantly, against COVID-19 and flu co-infections,” Dr. Wan said.

Future studies involving a wider geographic area and a more diverse population will be needed to provide more clarity on the prevalence of overall flu and COVID-19 coinfections and the effectiveness of both COVID-19 and flu vaccines.

“Testing for both flu and COVID-19 viruses in patients experiencing symptoms of respiratory illness and vaccinations against both viruses should continue to be encouraged,” he said.

The study, “SARS-CoV-2 and influenza co-infection: A cross sectional study in central Missouri during the 2021-2022 influenza season,” was published in the journal Virology.

Study: Children With Severe Epilepsy Should Receive Flu Vaccine

Children with a severe form of epilepsy should be vaccinated against the flu due to the high risk of seizures being triggered by an influenza infection, according to a new study.

The research, led by the Murdoch Children’s Research Institute and the University of Melbourne, found the safe administration of the seasonal influenza vaccine should be a priority in those with SCN1A-positive Dravet syndrome, given the likelihood of severe neurologic symptoms and complications such as worsening seizures, deteriorating language and motor skills, and even death after catching the flu.

Pediatric neurologist Katherine Howell from the Murdoch Children’s said the decision for parents to vaccinate children with this syndrome was complex because seizures could be triggered by both infection and vaccination. Dr. Howell said despite the syndrome being associated with high rates of prolonged seizures during infections, the impact of influenza had not been previously studied.

The research, published in Neurology, involved children with SCN1A-positive Dravet syndrome who had a confirmed influenza infection at The Royal Children’s and Austin Hospital. Researchers found 21 children caught influenza 24 times, with brain complications reported in 88% of cases. All presented to a hospital, with 75% recovering quickly, but death or long-term brain complications occurred in one in five infections. Among them, they received 60 influenza vaccinations, with most tolerating the vaccine well.

“Concerns about giving the flu vaccine and incomplete routine immunizations are common in this patient group due to the risk of seizures after vaccination,” Dr. Howell said. “However, because this syndrome is also associated with a high risk of seizures during infections, it highlights the critical need to protect patients from the complications of vaccine-preventable infections like the flu. Our research highlights that the benefits of flu vaccines for these children far outweighs the risks of seizures being triggered following vaccination.”

SCN1A-positive Dravet syndrome, the most common severe form of genetic epilepsy, occurs in one in 15,000 children.

University of Melbourne Professor Ingrid Scheffer said the findings would change clinical practice. “Identifying safe strategies and strongly encouraging influenza vaccination in children and adults with SCN1A-Dravet syndrome is critical.

“Prior to influenza vaccination, vaccine providers should review the child’s regular antiseizure medications and ensure a seizure management plan is in place. The use of additional antiseizure medications in the post vaccination period, such as benzodiazepines, is now recommended to reduce the risk of seizures following a vaccine and is becoming routine practice.”

Flu Shots Can Protect Patients With Heart Failure From Early Death

Flu shots can save the lives of people with cardiovascular disease by reducing cardiac complications as well as preventing influenza. An international study led by McMaster University researchers and published in The Lancet Global Health has found that influenza vaccines greatly reduce both pneumonia and cardiovascular complications in people with heart failure.

“If you have heart failure, you should get your flu shot because it can save your life—that is what we found in this study,” said the principal investigator, Mark Loeb, a McMaster professor of pathology and molecular medicine and a Hamilton infectious disease physician and microbiologist. “It is underappreciated that influenza vaccine can save people from cardiovascular death,” he added.

The study showed that over the entire year the influenza vaccine reduced pneumonia by 40% and hospitalization by 15% in patients with heart failure. During influenza season in the fall and winter, the influenza vaccine reduced deaths by 20% in these patients.

Data gathered during flu season also showed the vaccine helped protect against cardiovascular complications, such as heart attacks and strokes.

In a collaborative clinical trial between McMaster and the Population Health Research Institute (PHRI) of McMaster and Hamilton Health Sciences, investigators tracked more than 5,000 patients with heart failure in 10 countries across Africa, Asia, and the Middle East, where few people have regular influenza vaccination. They received either an influenza vaccine or a placebo annually between June 2015 and November 2021.

While the flu has long been associated with an increased risk of life-threatening cardiovascular events, Dr. Loeb said that people with heart failure are already vulnerable to poor health outcomes. Patients with the condition have a 50% chance of dying within 5 years, while 20% are hospitalized for cardiovascular complications every year.

“Importantly, we looked at low- and middle-income countries where 80% of cardiovascular disease occurs and where flu vaccination rates are low.”

Salim Yusuf, executive director of PHRI and an author of the study said, “The flu shot should be part of the standard practice in people with heart failure given how simple, inexpensive, and safe it is. Avoiding one sixth of deaths from heart disease and preventing hospitalizations makes it very cost effective, and that can have an important public health and clinical impact.”

The study is the first clinical trial of the flu vaccine’s effectiveness in patients with heart failure.

Common Viruses May Trigger Alzheimer’s Onset

Alzheimer’s disease can begin almost imperceptibly, often masquerading in the early months or years as forgetfulness that is common in older age. What causes the disease remains largely a mystery.

Researchers at Tufts University and the University of Oxford, using a three-dimensional human tissue culture model mimicking the brain, have shown that varicella zoster virus (VZV), which commonly causes chickenpox and shingles, may activate herpes simplex (HSV), another common virus, to set in motion the early stages of Alzheimer’s disease.

Normally HSV-1, one of the main variants of the virus, lies dormant within the neurons of the brain. When it is activated, it leads to accumulation of tau and amyloid-beta proteins and loss of neuronal function—signature features in patients with Alzheimer’s.

“Our results suggest one pathway to Alzheimer’s disease, caused by a VZV infection which creates inflammatory triggers that awaken HSV in the brain,” said Dana Cairns, a research associate in the Biomedical Engineering Department. “While we demonstrated a link between VZV and HSV-1 activation, it’s possible that other inflammatory events in the brain could also awaken HSV-1 and lead to Alzheimer’s disease.”

The study was published in the Journal of Alzheimer's Disease.

“We have been working off a lot of established evidence that HSV has been linked to increased risk of Alzheimer’s disease in patients,” said David Kaplan, Stern Family Professor of Engineering and chair of the Department of Biomedical Engineering at Tufts’ School of Engineering. One of the first to hypothesize a connection between herpes virus and Alzheimer’s disease is Ruth Itzhaki of the University of Oxford, who collaborated with the Kaplan laboratory on this study.

“We know there is a correlation between HSV-1 and Alzheimer’s disease, and some suggested involvement of VZV, but what we didn’t know is the sequence of events that the viruses create to set the disease in motion,” Dr. Kaplan said. “We think we now have evidence of those events.”

According to the World Health Organization, an estimated 3.7 billion people aged younger than 50 years have been infected with HSV-1—the virus that causes oral herpes. In most cases it is asymptomatic, lying dormant within nerve cells.

When activated, it can cause inflammation in nerves and skin, causing painful open sores and blisters. Most carriers, one in two Americans according to the CDC, will have very mild to no symptoms before the virus becomes dormant.

VZV is also extremely common, with about 95% of people having been infected before age 20 years. Many of those cases are expressed as chickenpox. VZV, which is a form of herpes virus, can also remain in the body, finding its way to nerve cells before then becoming dormant. Later in life, VZV can be reactivated to cause shingles, and one in three people will eventually develop a case of shingles in their lifetime.

The link between HSV-1 and Alzheimer’s disease only occurs when HSV-1 has been reactivated to cause sores, blisters, and other painful inflammatory conditions.

To better understand the cause-and-effect relationship between the viruses and Alzheimer’s disease, the Tufts researchers recreated brain-like environments in small, 6-millimeter-wide, donut-shaped sponges made of silk protein and collagen.

They populated the sponges with neural stem cells that grow and become functional neurons capable of passing signals to each other in a network, just as they do in the brain. Some of the stem cells also form glial cells, which are typically found in the brain and help keep the neurons alive and functioning.

The researchers found that neurons grown in the brain tissue can be infected with VZV, but that alone did not lead to the formation of the signature Alzheimer’s proteins tau and beta-amyloid. However, if the neurons already harbored quiescent HSV-1, the exposure to VZV led to a reactivation of HSV and a dramatic increase in tau and beta-amyloid proteins, and the neuronal signals begin to slow down.

“It’s a one-two punch of two viruses that are very common and usually harmless, but the laboratory studies suggest that if a new exposure to VZV wakes up dormant HSV-1, they could cause trouble,” said Dr. Cairns.

“It’s still possible that other infections and other pathways of cause and effect could lead to Alzheimer’s disease, and risk factors such as head trauma, obesity, or alcohol consumption suggest they may intersect at the reemergence of HSV in the brain,” she added.

The researchers observed that the VZV-infected samples started to produce a higher level of cytokines—proteins that are often involved in triggering an inflammatory response. Dr. Kaplan noted that VZV is known in many clinical cases to cause inflammation in the brain, which could possibly lead to activation of dormant HSV and increased inflammation. Repeat cycles of HSV-1 activation can lead to more inflammation in the brain, production of plaques, and accumulation of neuronal and cognitive damage.

A vaccine for VZV to prevent chickenpox and shingles has also been shown to considerably reduce the risk of dementia. It’s possible that the vaccine is helping to stop the cycle of viral reactivation, inflammation, and neuronal damage.

The researchers also noted the long-term neurologic effects that some COVID patients have experienced from severe acute respiratory syndrome coronavirus 2, particularly among the elderly, and that both VZV and HSV-1 can be reactivated after a COVID infection. Keeping an eye on possible follow-on cognitive effects and neurodegeneration would be advisable in these cases, they added.

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