Influenza infection is linked to a subsequent diagnosis of Parkinson’s disease (PD) more than 10 years later, resurfacing a long-held debate about whether infection increases the risk for movement disorders over the long-term.
In a large case-control study, investigators found the odds of PD were elevated by approximately 90% for PD that occurred more than 15 years after influenza infection and by more than 70% for PD occurring more than 10 years after the flu.
“This study is not definitive by any means, but it certainly suggests there are potential long-term consequences from influenza,” study investigator Noelle M. Cocoros, DSc, MPH, research scientist at Harvard Pilgrim Health Care Institute and Harvard Medical School, Boston, Massachusetts, told Medscape Medical News.
The study was published online October 25 in JAMA Neurology.
The debate about whether influenza is associated with PD has been going on as far back as the 1918 influenza pandemic, when experts documented parkinsonism in affected individuals.
Using data from the Danish patient registry, researchers identified 10,271 subjects diagnosed with PD during a 17-year period 2000-2016. Of these, 38.7% were female, and the mean age was 71.4 years.
They matched these subjects for age and sex to 51,355 controls without PD. Compared with controls, slightly fewer individuals with PD had chronic obstructive pulmonary disease (COPD) or emphysema, but there was a similar distribution of cardiovascular disease and various other conditions.
Researchers collected data on influenza diagnoses from inpatient and outpatient hospital clinics from 1977-2016. They plotted these by month and year on a graph, calculated the median number of diagnoses per month and identified peaks as those with more than threefold the median.
They categorized cases in groups related to the time between the infection and PD: more than 10 years, 10-15 years, and more than 15 years.
The time lapse accounts for a rather long “run-up” to PD, said Cocoros. There’s a sometimes decades-long preclinical phase before patients develop typical motor signs and a prodromal phase where they may present with nonmotor symptoms such as sleep disorders and constipation.
“We expected there would be at least 10 years between any infection and PD if there was an association present,” said Cocoros.
Investigators found an association between influenza exposure and PD diagnosis “that held up over time,” she said.
For more than 10 years before PD, the likelihood of a diagnosis for the infected compared with the unexposed was increased 73% (odds ratio [OR] 1.73; 95% CI, 1.11 – 2.71; P = .02) after adjusting for cardiovascular disease, diabetes, chronic obstructive pulmonary disease, emphysema, lung cancer, Crohn disease, and ulcerative colitis.
The odds increased with more time from 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 timeframe, the point estimate was reduced and the CI nonsignificant (OR, 1.33; 95% CI, 0.54 – 3.27; P = .53). This “is a little hard to interpret,” but could be a result of the small numbers, exposure misclassification, or because “the longer time interval is what’s meaningful,” said Cocoros.
Potential COVID-related PD Surge?
In a sensitivity analysis, researchers looked at peak infection activity. “We wanted to increase the likelihood of these diagnoses representing actual infection,” Cocoros noted.
Here, the OR was still elevated at more than 10 years, but the CI was quite wide and included 1 (OR, 1.52; 95% CI, 0.80 – 2.89; P = .21). “So the association holds up, but the estimates are quite unstable,” said Cocoros.
Researchers examined associations with numerous other infection types, but did not see the same trend over time. Some infections, for example, gastrointestinal infections and septicemia, were associated with PD within 5 years, but most associations appeared to be null after more than 10 years.
“There seemed to be associations earlier between the infection and PD, which we interpret to suggest there’s actually not a meaningful association,” said Cocoros.
An exception might be urinary tract infections (UTIs), where after 10 years, the adjusted OR was 1.19 (95% CI 1.01 – 1.40). Research suggests patients with PD often have UTIs and neurogenic bladder.
“It’s possible that UTIs could be an early symptom of PD rather than a causative factor,” said Cocoros.
It’s unclear how influenza might lead to PD but it could be that the virus gets into the central nervous system, resulting in neuroinflammation. Cytokines generated in response to the influenza infection might damage the brain.
“The infection could be a “primer” or an initial “hit” to the system, maybe setting people up for PD,” said Cocoros.
As for the current COVID-19 pandemic, some experts are concerned about a potential surge in PD cases in decades to come, with some calling for prospective monitoring of patients with this infection, said Cocoros.
However, she noted that infections don’t account for all PD cases and that genetic and environmental factors also influence risk.
Many individuals who contract influenza don’t seek medical care or get tested, so it’s possible the study counted those who had the infection as unexposed. Another potential study limitation was that small numbers for some infections, for example, H pylori and hepatitis C, limited the ability to interpret results
“Exciting and Important” Findings
Commenting on the research 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 reinvigorated interest” in the role of infection in PD.
However, the study had some limitations, an important one being lack of accounting for confounding factors, including environmental factors, she said. Exposure to pesticides, living in a rural area, drinking well water, and having had a head injury may increase PD risk, whereas high intake of caffeine, nicotine, alcohol, and nonsteroidal anti-inflammatory drugs might lower the risk.
The study also didn’t take into account exposure to multiple microbes or “infection burden,” said Wagle Shukla, who was not involved in the current study. In addition, as the data are from a single country with exposure to specific influenza strains, application of the findings elsewhere may be limited.
Wagle Shukla also noted that a case-control design “isn’t ideal” from an epidemiological perspective. “Future studies should involve large cohorts followed longitudinally.”
The study was supported by grants from the Lundbeck Foundation and the Augustinus Foundation. Cocoros has disclosed no relevant financial relationships. Several co-authors have disclosed relationships with industry. The full list can be found with the original article.
JAMA Neurology. Published October 25, 2021. Abstract