Influenza and Parkinson’s: How Big Is the Risk? An Updated Meta-Analysis
Making sense of the complicated epidemiological link between influenza and Parkinson's disease.
Everyone knows the U.S. is experiencing one of the worst flu seasons in 15 years. From October 2024 to February 2025, about 50 million people were infected, almost a million were hospitalized, and almost 100,000 died (Figure 1). Certain regions in Europe and Asia are also experiencing one of the most aggressive flu seasons this year. Japan, in particular, recorded its worst flu season since it started keeping records 25 years ago in 1999.
These recent flu outbreaks are primarily driven by the avian influenza A virus (IAV). This strain circulates among wild birds and poultry, which can spread to humans. Unlike the influenza B virus (IBV), which is generally milder and mainly infects humans, the pandemic risk of IAV is high due to its ability to reassort with animal influenza strains, leading to new, unpredictable strains. While both IAV and IBV can drive seasonal flu, IAV is often more serious. So, I’m mainly referring to IAV when I write influenza virus in this article.
Amidst the ongoing flu outbreaks, I remember a relevant article I wrote over a year ago titled “Solving the Cause of Parkinson’s Disease, As An Academic in This Field.” In it, I described the involvement of infectious agents in the multi-hit hypothesis of Parkinson’s Disease (PD). Based on biological mechanisms and epidemiological evidence, the influenza virus was among the highly suspected culprits in the etiology of PD. But in this article, I want to revisit and explore the epidemiological link between influenza and PD more deeply—to understand the extent to which influenza can raise the risk of PD.
Historical Observations
The link between influenza and PD dates back to observations made after the 1918 influenza pandemic (popularly known as the Spanish flu). During the following decade, there was a surge in neurological complications, particularly encephalitis lethargica (EL), a neuroinflammatory disorder with symptoms of fever, lethargy, mental confusion, and motor control problems. It’s estimated that EL affected over a million people globally by 1930.
(Although the 1918 influenza virus is highly suspected of causing the rise in EL cases based on circumstantial and biological plausibility, this has not been definitively proven. But that’s a topic for another article.)
About 80% of EL survivors developed Parkinsonism symptoms that are nearly indistinguishable from clinical PD, such as tremors, slow movement, and masked facial expressions (Figure 2). Dopamine-modulating drugs used to treat PD were successful at treating post-EL Parkinsonism as well. Research later found that individuals born between 1888 and 1924—who were either infants or young adults during the pandemic—had a 2-3 times higher risk of developing PD later in life than those born before 1888 or after 1924.
Laboratory findings also noted the presence of influenza virus proteins and degenerated motor neurons in the brains of victims of the 1918 influenza pandemic, particularly in the midbrain regions involved in motor control. This led to speculation that the influenza virus may trigger long-term neurodegenerative effects in the brain’s motor control system, which may eventually lead to or increase the risk of PD development.
Since then, modern epidemiological studies have reinforced the link between influenza infection and PD, as the following sections will explore.
Modern Observations (as of 2019)
First, let’s begin with a 2020 meta-analysis that systematically screened the existing literature in October 2019 for any study examining the association between infections and the risk of PD. They derived 23 studies for synthesis in their meta-analysis, which reported a significant rise in PD risk following infections with Helicobacter pylori, hepatitis C virus, Malassezia fungi, and pneumoniae—but not influenza virus, herpes virus, hepatitis B virus, scarlet fever, mumps virus, chicken pox, pertussis, and measles. Setting aside other pathogens (as they are all topics for another article), let’s see why the influenza virus was not associated with PD in this meta-analysis.
In their meta-analysis, data from four studies investigating the link between influenza and PD were combined, yielding an odds ratio (OR) of 1.95 with a 95% confidence interval (95% CI) of 0.77 to 4.94 (Figure 3). While an OR of 1.95 suggests a 95% increase in the odds of developing PD following influenza, the result is not statistically significant since the 95% CI crosses 1.0.
This is because an OR of 1.0 means neutral effect (i.e., >1 means increase and <1 means decrease), and the 95% CI represents the range within which the true OR is expected to lie 95% of the time.
So, even though the effect size indicates a nearly 2-fold increase in risk, the wide CI suggests uncertainty, often due to variability between studies. In essence, the trend is there —especially when the upper bound of the 95% CI reaches 4.94 (indicating an almost fivefold increase in risk)—but it lacks the statistical power to confirm a definitive association.
Now, let’s take a brief look at the individual studies in the meta-analysis:
Harris et al. (2012), Canada, recruited 403 PD cases and 405 non-PD controls to compare their prior influenza exposure. The PD cases were 2 times more likely to have caught severe influenza (OR = 2.01, 95% CI = 1.16 to 3.48), mainly within 5 years before the PD diagnosis (OR = 2.02; 95% CI = 1.14 to 3.59). The risk was attenuated for influenza infection occurring ≥10 years before the PD diagnosis (OR = 1.74; 95% CI = 0.97 to 3.12).
Sasco and Paffenbarger (1985), U.S., tracked the college records of 50,002 former students and reported that influenza infection during college years was not statistically significant in influencing the risk of PD in old age (OR = 1.1; 95% CI = 0.69 to 1.8). But decades have passed between influenza exposure and PD diagnosis in the study, which likely missed the timeframe in which influenza raises the risk of PD.
Vlajinac et al. (2013), Serbia, recruited 110 PD cases and 220 non-PD controls to compare their prior influenza exposure. The PD cases were 8 times more likely to have caught influenza in their lifetime compared to controls (OR = 8.01, 95% CI = 4.61 to 13.92). However, the timeframe of the influenza exposure was not reported.
Toovey et al. (2011), U.K., analyzed the health records of 26,713 PD cases and 4.6 million controls, finding no significant association between prior influenza infection and PD (OR = 1.13, 95% CI = 0.94 to 1.34). But this study only tracked influenza infection within 2 years before the PD diagnosis, which may be too short a window to capture long-term effects.
(That said, the Toovey et al. study did find a significant association between prior influenza and Parkinson’s-like symptoms (OR = 1.45; 95% CI = 1.25 to 1.68), suggestive of a pre-clinical phase that does not yet meet the requirement for clinical PD. So, it can be speculated that with a longer follow-up period, some of these individuals could progress to PD.)
Of the four studies discussed in the meta-analysis, only the Harris et al. (2012) study is reliable, as it provides both the risk power (effect size) and risk period (risk window). The Sasco and Paffenbarger (1985) study only tracked early-life influenza exposure, Vlajinax et al. (2023) study did not provide the risk period, and Toovey et al. (2011) study only tracked recent influenza exposure.
So, we need to look at more recent studies to derive a better understanding of the relationship between influenza and PD.
Modern Observations (as of 2025)
Not much development has occurred since, to be honest. Only two new studies have been published after the 2020 meta-analysis:
Cocoros et al. (2021), Denmark, examined the health records of 10,271 individuals with PD and 51,355 non-PD controls. Those with PD were 1.7-fold more likely to have caught influenza 10 years or more before the PD diagnosis (OR = 1.73; 95% CI = 1.11 to 2.71). The risk was even greater for influenza occurring 15 years or more before the PD diagnosis (OR = 1.91; 95% CI = 1.14-3.19). Oddly, no significant association was found for influenza infection within 10 years of PD and for lifetime influenza regardless of exposure time (OR = 1.26; 95% CI = 0.89 to 1.78).
Levine et al. (2023), U.S., conducted the largest study on infections and neurodegenerative diseases, analyzing medical records from >450,000 individuals in the Finnish and U.K. biobanks. Focusing on influenza and PD, the study found that individuals with PD were 2–3 times more likely to have had influenza within 5 years before diagnosis. The association was strongest for influenza with pneumonia occurring within one year before PD (OR = 6.2; 95% CI = 4.24–9.05). But the link became non-significant for influenza occurring 15 years or more before PD diagnosis. For lifetime influenza, regardless of exposure time, the risk of PD was significant at 1.8-fold in the Finnish cohort and 4.3-fold in the U.K. cohort.
(Note: For a better understanding of what OR and 95% CI mean, please refer to the section on “Modern Observations (as of 2019)” above).
Admittedly, it’s difficult to reconcile these findings. Cocoros et al. (2021) showed that longer-term influenza infection (i.e., ≥ 10-15 years) is more important in contributing to PD risk, whereas Levine et al. found a shorter risk period (i.e., ≤ 5 years) where influenza may increase the risk of PD.
The study authors also noted these discrepancies, suggesting that differences in circulating influenza strains may vary in their influence on PD risk. Some strains may be more aggressive and accelerate the risk of PD sooner, while others may act like a slower burn. Unfortunately, none of the epidemiological studies discussed identified the specific influenza strains involved.
Moving forward, the best approach is to synthesize all the existing studies in an updated meta-analysis, regardless of the risk period, to identify the overall trend of the link between influenza infection and the risk of PD.
This approach accounts for the diversity across studies, such as variations in follow-up duration, influenza strain, and population characteristics. Instead of performing a subgroup analysis—which can introduce bias due to smaller sample sizes and reduced statistical power—this method ensures a more generalizable conclusion in line with research best practices.
As there’s no updated meta-analysis after the one by Wang et al. (2020) in the existing literature, I performed one, synthesizing all the six abovementioned studies to identify the association between lifetime influenza exposure and the risk of PD. I identified a statistically significant pooled odds ratio of 2.1 (OR = 2.1; 95% CI = 1.18 to 3.44), indicating that lifetime influenza exposure raises the risk of PD slightly over twofold, i.e., 2.1-fold (Figure 4).
Putting the Effect Size in Context
Now, what does an odds ratio of 2.1 mean for us?
Let’s first clarify that the odds ratio is often interpreted synonymously with the risk ratio, especially when estimating a rare outcome with a prevalence of less than 10%. According to the most recent estimate by a 2024 meta-analysis, the global prevalence of Parkinson’s disease (PD) is rare, affecting only 1.51 cases per 1,000 individuals and 9.34 cases per 1000 individuals older than 60. PD is an age-related disease, after all. Percentage-wise, that’s 0.15% and 0.93% prevalence for all ages and >60 years, respectively.
As a rough calculation, we can treat them as a 0.15% risk of developing PD at any age and 0.93% if you are 60 years old and above. A 2.1-fold increase in risk (OR = 2.1) means experiencing a prior influenza infection, regardless of when, will double the risk slightly to 0.32% and 1.96%, respectively.
Of course, <2% is still considered low risk, as it also means other variables account for the remaining 98% of the risk. Ultimately, PD is a multifactorial disease influenced by various risk factors, such as age, sex, genetics, lifestyle, head trauma/injuries, environmental toxins, and, of course, pathogens, most notably influenza virus, H. pylori, and hepatitis C virus.
Although the contributions of these individual risk factors may not be great, having multiple risk factors simultaneously could drastically increase the risk of PD and ultimately determine who develops it. To better understand how synergistic risks work, let’s move on to the biological underpinnings.
The Biological Underpinnings
In my previous article, “Solving the Cause of Parkinson’s Disease, As An Academic in This Field,” I described a 2017 study showing that prior influenza virus infection could synergize with MPTP to cause PD in mice. MPTP is a neurotoxin structurally similar to the common pesticides rotenone and paraquat. Specifically, MPTP produced greater neurodegeneration in mice previously infected with influenza, suggesting that prior influenza, even if resolved, could sensitize the brain to a second insult, i.e., pesticides.
Indeed, it’s well-established that chronic exposure to pesticides, such as rotenone and paraquat, put farmers at about 2.5-fold increased risk of PD than non-farmers. Such pesticides are still being sold, and thousands of farmers with PD have sued pesticide manufacturers in the U.S. for prioritizing sales over safety communication.
Similar to the 2.1-fold increased risk from a prior influenza infection, a 2.5-fold increased risk from pesticide exposure is not huge. But because the biological mechanisms underpinning these risk factors synergize, their combined effect is multiplicative at minimum. This is similar to the synergistic risk factors of family history and overweight in type 2 diabetes, as well as high cholesterol and hypertension in cardiovascular diseases.
Therefore, an individual with a history of influenza and chronic pesticide exposure would have at least a 5.2-fold increased risk of PD (2.5 × 2.1 = 5.25). That would increase the baseline risk of PD from 0.15% to at least 0.79% for all ages and from 0.93% to at least 4.88% for those over 60.
I mention ‘at least’ because when risk factors act synergistically, their combined impact often exceeds a simple multiplicative effect.
Now, consider additional risk factors—such as old age, male sex, genetic predisposition, prior head trauma, or H. pylori infection—layered on top of these exposures. The cumulative risk becomes exponentially higher, making it increasingly evident who is most vulnerable to developing PD.
Of course, that’s easier said than done. At present, we don’t have the perfect equation to predict with absolute certainty if someone will develop PD. Everyone’s condition and risk profile are different, especially when we have to take protective factors for PD (e.g., exercise, coffee consumption, certain genetic variants, vagotomy, and vaccination) into account as well.
What’s Next?
Speaking of vaccination, I initially planned to explore its potential role in reducing PD risk. But preliminary reading tells me that influenza vaccines are primarily studied for their protective effects against dementia rather than PD. Given this, I’ll first examine the link between influenza and dementia in my next article, before diving into whether influenza vaccination may offer any neuroprotective benefits against neurodegenerative diseases like dementia and PD.
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