Influenza linked to long-term increased risk of Parkinson’s disease

The influenza infection is linked to a subsequent diagnosis of Parkinson’s disease (PD) more than 10 years later, resurfacing a long-standing debate about whether the infection increases the risk of long-term movement disorders. term.

In a large case-control study, investigators found that the odds of PD were about 90% high for PD occurring more than 15 years after influenza infection and over 70% for PD occurring over 10 years. years after the flu.

Dr Noëlle Cocoros

“This study is by no means definitive, but it certainly suggests that there are potential long-term consequences of influenza,” study investigator Noelle M. Cocoros, DSc, MPH, researcher at Harvard Pilgrim Health Care Institute and at Harvard Medical School, Boston, Massachusetts, said Medscape Medical News.

The study was published online on October 25 in JAMA Neurology.

Ongoing debate

The debate over whether the flu is associated with PD dates back to the 1918 influenza pandemic, when experts documented parkinsonism in those affected.

Using data from the Danish Patient Registry, researchers identified 10,271 subjects diagnosed with PD over a 17-year period 2000-2016. Among them, 38.7% were women and the average age was 71.4 years.

They matched these subjects for age and sex to 51,355 controls without PD. Compared to controls, slightly fewer people with PD had chronic obstructive pulmonary disease (COPD) or emphysema, but there was a similar distribution of cardiovascular disease and various other conditions.

The researchers collected data on influenza diagnoses in inpatient and outpatient clinics from 1977 to 2016. They plotted them by month and year on a graph, calculated the median number of diagnoses per month, and identified the peaks as those with more than three times the median.

They classified the cases into groups related to the time between infection and PD: over 10 years, 10-15 years and over 15 years.

The lapse of time explains quite a long “preparation” towards PD, Cocoros said. There is sometimes a preclinical phase of several decades before patients develop typical motor signs and a prodromal phase where they may present with non-motor symptoms such as sleep disturbances and constipation.

“We expected there would be at least 10 years between any infection and PD if there was an association present,” Cocoros said.

Investigators found an association between exposure to influenza and the diagnosis of PD “that lasted over time,” she said.

For more than 10 years before PD, the likelihood of a diagnosis for those infected versus unexposed was increased by 73% (odds ratio [OR] 1.73; 95% CI, 1.11 – 2.71; P = 0.02) after adjusting for cardiovascular disease, diabetes, chronic obstructive pulmonary disease, emphysema, lung cancer, Crohn’s disease and ulcerative colitis.

The odds increased with the time since infection. For more than 15 years, the adjusted OR was 1.91 (95% CI: 1.14 – 3.19; P = .01).

However, for the 10 to 15 year period, the point estimate was reduced and the CI not significant (OR, 1.33; 95% CI, 0.54 – 3.27; P = 0.53). This “is a bit difficult to interpret,” but could be the result of the small numbers, misclassification of exposure, or because “the longer time interval is what is significant,” Cocoros said. .

Potential increase in PD linked to COVID?

In a sensitivity analysis, the researchers looked at peak infection activity. “We wanted to increase the likelihood that these diagnoses represent an actual infection,” noted Cocoros.

Here, the OR was still high at over 10 years, but the CI was quite large and included 1 (OR, 1.52; 95% CI, 0.80 – 2.89; P = .21). “So the association is holding up, but the estimates are quite volatile,” Cocoros said.

Researchers looked at associations with many other types of infection, but didn’t see the same pattern over time. Some infections, for example gastrointestinal infections and sepsis, were associated with PD within 5 years, but most associations appeared to be zero after more than 10 years.

“There seemed to be associations earlier between infection and PD, which we interpret to suggest that there is in fact no significant association,” Cocoros said.

An exception could be urinary tract infections (UTIs), where after 10 years the adjusted OR was 1.19 (95% CI 1.01 – 1.40). Research suggests that patients with PD often have UTIs and a neurogenic bladder.

“It is possible that UTIs are an early symptom of PD rather than a causative factor,” Cocoros said.

It is not known how the flu could lead to PD, but it could be that the virus enters the central nervous system, causing neuroinflammation. Cytokines generated in response to influenza infection could damage the brain.

“The infection could be a ‘primer’ or a ‘first’ blow to the system, perhaps preparing people for Parkinson’s disease,” Cocoros said.

Regarding the current COVID-19 pandemic, some experts are concerned about a potential increase in PD cases in the coming decades, with some calling for prospective surveillance of patients with this infection, Cocoros said.

However, she noted that infections do not account for all cases of PD and that genetic and environmental factors also influence risk.

Many people who contract the flu do not seek medical attention or get tested, so it is possible that the study counted those infected as unexposed. Another potential limitation of the study was that small numbers for some infections, for example, H pylori and hepatitis C, limits the ability to interpret the results

“Exciting and important” discoveries

Commenting on the search for Medscape Medical News, Aparna Wagle Shukla, MD, professor, Norman Fixel Institute for Neurological Diseases, University Of Florida, Gainesville, said the results amid the current pandemic are “exciting and important” and “have rekindled interest” in the role of infection in PD.

However, the study had some limitations, an important one being the failure to take into account confounding factors, including environmental factors, she said. Exposure to pesticides, living in a rural area, drinking well water and having suffered a head injury can increase the risk of PD, while high consumption of caffeine, nicotine, alcohol and nonsteroidal anti-inflammatory drugs may reduce the risk.

The study also did not take into account exposure to multiple microbes or the “burden of infections,” said Wagle Shukla, who was not involved in the current study. In addition, because the data comes from a single country exposed to specific influenza strains, the application of the results elsewhere may be limited.

Wagle Shukla also noted that a case-control design “is not ideal” from an epidemiological point of view. “Future studies should involve large cohorts followed longitudinally.”

The study was supported by grants from the Lundbeck Foundation and the Augustinus Foundation. Cocoros did not disclose any relevant financial relationship. Several co-authors have disclosed relationships with the industry. The full list can be found with the original article.

JAMA Neurology. Published on October 25, 2021. Summary

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