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Long-term Risk of Parkinson Disease Following Influenza and Other Infections

Educational Objective
To examine whether prior influenza and other infections are associated with Parkinson disease.
1 Credit CME
Key Points

Question  Is influenza or other infection associated with Parkinson disease?

Findings  In this case-control study of all Danish citizens with Parkinson disease between 2000 and 2016, unlike most other infections, influenza was associated with Parkinson disease more than 10 years after infection.

Meaning  Influenza infection may increase the long-term risk of developing Parkinson disease.


Importance  Influenza has been associated with the risk of developing Parkinson disease, but the association is controversial.

Objective  To examine whether prior influenza and other infections are associated with Parkinson disease more than 10 years after infection.

Design, Setting, and Participants  This case-control study used data from 1977 to 2016 from the Danish National Patient Registry. All individuals with Parkinson disease, excluding those with drug-induced parkinsonism, were included and matched to 5 population controls on sex, age, and date of Parkinson diagnosis. Data were analyzed from December 2019 to September 2021.

Exposures  Infections were ascertained between 1977 and 2016 and categorized by time from infection to Parkinson disease diagnosis. To increase specificity of influenza diagnoses, influenza exposure was restricted to months of peak influenza activity.

Main Outcomes and Measures  Parkinson disease diagnoses were identified between January 1, 2000, and December 31, 2016. Crude and adjusted odds ratios (ORs) and 95% CIs were calculated by conditional logistic regression overall and stratified by time between infection and Parkinson disease (5 years or less, more than 5 to 10 years, more than 10 years).

Results  Of 61 626 included individuals, 23 826 (38.7%) were female, and 53 202 (86.3%) were older than 60 years. A total of 10 271 individuals with Parkinson disease and 51 355 controls were identified. Influenza diagnosed at any time during a calendar year was associated with Parkinson disease more than 10 years later (OR, 1.73; 95% CI, 1.11-2.71). When influenza exposure was restricted to months of highest influenza activity, an elevated OR with a wider confidence interval was found (OR, 1.52; 95% CI, 0.80-2.89). There was no evidence of an association with any type of infection more than 10 years prior to Parkinson disease (OR, 1.04; 95% CI, 0.98-1.10). Several specific infections yielded increased odds of Parkinson disease within 5 years of infection, but results were null when exposure occurred more than 10 years prior.

Conclusions and Relevance  In this case-control study, influenza was associated with diagnoses of Parkinson disease more than 10 years after infection. These observational data suggest a link between influenza and Parkinson disease but do not demonstrate causality. While other infections were associated with Parkinson disease diagnoses soon after infection, null associations after more than 10 years suggest these shorter-term associations are not causal.

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Article Information

Accepted for Publication: September 7, 2021.

Published Online: October 25, 2021. doi:10.1001/jamaneurol.2021.3895

Corresponding Author: Noelle M. Cocoros, DSc, Department of Population Medicine at Harvard Medical School and Harvard Pilgrim Health Care Institute, 401 Park Dr, Ste 401E, Boston, MA 02215 (noelle_cocoros@harvardpilgrim.org).

Author Contributions: Ms Szépligeti and Mr Szentkúti had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Cocoros, Svensson, Szentkúti, Borghammer, Sørensen, Henderson.

Acquisition, analysis, or interpretation of data: Cocoros, Svensson, Szépligeti, Vestergaard, Szentkúti, Thomsen, Sørensen.

Drafting of the manuscript: Cocoros, Svensson, Szentkúti, Borghammer.

Critical revision of the manuscript for important intellectual content: Cocoros, Szépligeti, Vestergaard, Szentkúti, Thomsen, Borghammer, Sørensen, Henderson.

Statistical analysis: Cocoros, Szépligeti, Szentkúti, Sørensen.

Obtained funding: Svensson, Sørensen.

Administrative, technical, or material support: Vestergaard, Sørensen.

Study supervision: Vestergaard, Borghammer, Sørensen.

Conflict of Interest Disclosures: Dr Svensson has received funding from the Augustinus Foundation. Dr Vestergaard has received grants from Lundbeck Foundation and Augustinus Foundation. Dr Henderson has received grants from the National Institutes of Health and personal fees from the National Institutes of Health, Canadian Consortium on Neurodegeneration in Aging, and Aarhus University. No other disclosures were reported.

Funding/Support: The project was supported by grants from the Lundbeck Foundation and the Augustinus Foundation. Dr Henderson was supported by grant P30 AG066515 from the National Institutes of Health.

Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Postuma  RB , Berg  D , Stern  M ,  et al.  MDS clinical diagnostic criteria for Parkinson’s disease.   Mov Disord. 2015;30(12):1591-1601. doi:10.1002/mds.26424PubMedGoogle ScholarCrossref
Wirdefeldt  K , Adami  HO , Cole  P , Trichopoulos  D , Mandel  J .  Epidemiology and etiology of Parkinson’s disease: a review of the evidence.   Eur J Epidemiol. 2011;26(suppl 1):S1-S58. doi:10.1007/s10654-011-9581-6PubMedGoogle ScholarCrossref
Tysnes  OB , Storstein  A .  Epidemiology of Parkinson’s disease.   J Neural Transm (Vienna). 2017;124(8):901-905. doi:10.1007/s00702-017-1686-yPubMedGoogle ScholarCrossref
Pringsheim  T , Jette  N , Frolkis  A , Steeves  TD .  The prevalence of Parkinson’s disease: a systematic review and meta-analysis.   Mov Disord. 2014;29(13):1583-1590. doi:10.1002/mds.25945PubMedGoogle ScholarCrossref
Vestergaard  SV , Rasmussen  TB , Stallknecht  S ,  et al.  Occurrence, mortality and cost of brain disorders in Denmark: a population-based cohort study.   BMJ Open. 2020;10(11):e037564. doi:10.1136/bmjopen-2020-037564PubMedGoogle Scholar
von Campenhausen  S , Bornschein  B , Wick  R ,  et al.  Prevalence and incidence of Parkinson’s disease in Europe.   Eur Neuropsychopharmacol. 2005;15(4):473-490. doi:10.1016/j.euroneuro.2005.04.007PubMedGoogle ScholarCrossref
Savica  R , Grossardt  BR , Bower  JH , Ahlskog  JE , Rocca  WA .  Time trends in the incidence of Parkinson disease.   JAMA Neurol. 2016;73(8):981-989. doi:10.1001/jamaneurol.2016.0947PubMedGoogle ScholarCrossref
Savica  R , Rocca  WA , Ahlskog  JE .  When does Parkinson disease start?   Arch Neurol. 2010;67(7):798-801. doi:10.1001/archneurol.2010.135PubMedGoogle ScholarCrossref
Limphaibool  N , Iwanowski  P , Holstad  MJV , Kobylarek  D , Kozubski  W .  Infectious etiologies of parkinsonism: pathomechanisms and clinical implications.   Front Neurol. 2019;10:652. doi:10.3389/fneur.2019.00652PubMedGoogle ScholarCrossref
Olsen  LK , Dowd  E , McKernan  DP .  A role for viral infections in Parkinson’s etiology?   Neuronal Signal. 2018;2(2):NS20170166. doi:10.1042/NS20170166PubMedGoogle Scholar
Moore  G .  Influenza and Parkinson’s disease.   Public Health Rep. 1977;92(1):79-80.PubMedGoogle Scholar
Henry  J , Smeyne  RJ , Jang  H , Miller  B , Okun  MS .  Parkinsonism and neurological manifestations of influenza throughout the 20th and 21st centuries.   Parkinsonism Relat Disord. 2010;16(9):566-571. doi:10.1016/j.parkreldis.2010.06.012PubMedGoogle ScholarCrossref
Poskanzer  DC , Schwab  RS .  Cohort analysis of Parkinson’s syndrome: evidence for a single etiology related to subclinical infection about 1920.   J Chronic Dis. 1963;16(9):961-973. doi:10.1016/0021-9681(63)90098-5PubMedGoogle ScholarCrossref
Dourmashkin  RR .  What caused the 1918-30 epidemic of encephalitis lethargica?   J R Soc Med. 1997;90(9):515-520. doi:10.1177/014107689709000916PubMedGoogle ScholarCrossref
Bond  M , Bechter  K , Müller  N , Tebartz van Elst  L , Meier  U-C .  A role for pathogen risk factors and autoimmunity in encephalitis lethargica?   Prog Neuropsychopharmacol Biol Psychiatry. 2021;109:110276. doi:10.1016/j.pnpbp.2021.110276PubMedGoogle Scholar
Estupinan  D , Nathoo  S , Okun  MS .  The demise of Poskanzer and Schwab’s influenza theory on the pathogenesis of Parkinson’s disease.   Parkinsons Dis. 2013;2013:167843. doi:10.1155/2013/167843PubMedGoogle Scholar
Smeyne  RJ , Noyce  AJ , Byrne  M , Savica  R , Marras  C .  Infection and risk of Parkinson’s disease.   J Parkinsons Dis. 2021;11(1):31-43.PubMedGoogle ScholarCrossref
Schmidt  M , Schmidt  SAJ , Adelborg  K ,  et al.  The Danish health care system and epidemiological research: from health care contacts to database records.   Clin Epidemiol. 2019;11:563-591. doi:10.2147/CLEP.S179083PubMedGoogle ScholarCrossref
Schmidt  M , Pedersen  L , Sørensen  HT .  The Danish Civil Registration System as a tool in epidemiology.   Eur J Epidemiol. 2014;29(8):541-549. doi:10.1007/s10654-014-9930-3PubMedGoogle ScholarCrossref
Schmidt  M , Schmidt  SA , Sandegaard  JL , Ehrenstein  V , Pedersen  L , Sørensen  HT .  The Danish National Patient Registry: a review of content, data quality, and research potential.   Clin Epidemiol. 2015;7:449-490. doi:10.2147/CLEP.S91125PubMedGoogle Scholar
Johannesdottir  SA , Horváth-Puhó  E , Ehrenstein  V , Schmidt  M , Pedersen  L , Sørensen  HT .  Existing data sources for clinical epidemiology: the Danish National Database of Reimbursed Prescriptions.   Clin Epidemiol. 2012;4:303-313. doi:10.2147/CLEP.S37587PubMedGoogle Scholar
Lee  H-S , Lobbestael  E , Vermeire  S , Sabino  J , Cleynen  I .  Inflammatory bowel disease and Parkinson’s disease: common pathophysiological links.   Gut. 2021;70(2):408-417.PubMedGoogle Scholar
Jacobs  BM , Belete  D , Bestwick  J ,  et al.  Parkinson’s disease determinants, prediction and gene-environment interactions in the UK Biobank.   J Neurol Neurosurg Psychiatry. 2020;91(10):1046-1054. doi:10.1136/jnnp-2020-323646PubMedGoogle ScholarCrossref
Li  X , Li  W , Liu  G , Shen  X , Tang  Y .  Association between cigarette smoking and Parkinson’s disease: a meta-analysis.   Arch Gerontol Geriatr. 2015;61(3):510-516. doi:10.1016/j.archger.2015.08.004PubMedGoogle ScholarCrossref
Ritz  B , Ascherio  A , Checkoway  H ,  et al.  Pooled analysis of tobacco use and risk of Parkinson disease.   Arch Neurol. 2007;64(7):990-997. doi:10.1001/archneur.64.7.990PubMedGoogle ScholarCrossref
Ferini-Strambi  L , Oertel  W , Dauvilliers  Y ,  et al.  Autonomic symptoms in idiopathic REM behavior disorder: a multicentre case-control study.   J Neurol. 2014;261(6):1112-1118. doi:10.1007/s00415-014-7317-8PubMedGoogle ScholarCrossref
Su  CM , Kung  CT , Chen  FC ,  et al.  Manifestations and outcomes of patients with Parkinson’s disease and serious infection in the emergency department.   Biomed Res Int. 2018;2018:6014896. doi:10.1155/2018/6014896PubMedGoogle Scholar
Gerlach  OH , Winogrodzka  A , Weber  WE .  Clinical problems in the hospitalized Parkinson’s disease patient: systematic review.   Mov Disord. 2011;26(2):197-208. doi:10.1002/mds.23449PubMedGoogle ScholarCrossref
Ginsberg  D .  The epidemiology and pathophysiology of neurogenic bladder.   Am J Manag Care. 2013;19(10)(suppl):s191-s196.PubMedGoogle Scholar
Rogers  MA , Fries  BE , Kaufman  SR , Mody  L , McMahon  LF  Jr , Saint  S .  Mobility and other predictors of hospitalization for urinary tract infection: a retrospective cohort study.   BMC Geriatr. 2008;8:31. doi:10.1186/1471-2318-8-31PubMedGoogle ScholarCrossref
Mahajan  A , Balakrishnan  P , Patel  A ,  et al.  Epidemiology of inpatient stay in Parkinson’s disease in the United States: insights from the Nationwide Inpatient Sample.   J Clin Neurosci. 2016;31:162-165. doi:10.1016/j.jocn.2016.03.005PubMedGoogle ScholarCrossref
Martinez-Ramirez  D , Velazquez-Avila  ES , Almaraz-Espinoza  A ,  et al.  Lower urinary tract and gastrointestinal dysfunction are common in early Parkinson’s disease.   Parkinsons Dis. 2020;2020:1694547. doi:10.1155/2020/1694547PubMedGoogle Scholar
Fereshtehnejad  S-M , Yao  C , Pelletier  A , Montplaisir  JY , Gagnon  J-F , Postuma  RB .  Evolution of prodromal Parkinson’s disease and dementia with Lewy bodies: a prospective study.   Brain. 2019;142(7):2051-2067. doi:10.1093/brain/awz111PubMedGoogle ScholarCrossref
Liu  B , Gao  HM , Hong  JS .  Parkinson’s disease and exposure to infectious agents and pesticides and the occurrence of brain injuries: role of neuroinflammation.   Environ Health Perspect. 2003;111(8):1065-1073. doi:10.1289/ehp.6361PubMedGoogle ScholarCrossref
Marras  C , Lang  AE , Austin  PC , Lau  C , Urbach  DR .  Appendectomy in mid and later life and risk of Parkinson’s disease: a population-based study.   Mov Disord. 2016;31(8):1243-1247. doi:10.1002/mds.26670PubMedGoogle ScholarCrossref
Svensson  E , Horváth-Puhó  E , Stokholm  MG , Sørensen  HT , Henderson  VW , Borghammer  P .  Appendectomy and risk of Parkinson’s disease: a nationwide cohort study with more than 10 years of follow-up.   Mov Disord. 2016;31(12):1918-1922. doi:10.1002/mds.26761PubMedGoogle ScholarCrossref
Ishizuka  M , Shibuya  N , Takagi  K ,  et al.  Appendectomy does not increase the risk of future emergence of Parkinson’s disease: a meta-analysis.   Am Surg. Published online January 30, 2021.PubMedGoogle Scholar
Wang  H , Liu  X , Tan  C ,  et al.  Bacterial, viral, and fungal infection-related risk of Parkinson’s disease: meta-analysis of cohort and case-control studies.   Brain Behav. 2020;10(3):e01549. doi:10.1002/brb3.1549PubMedGoogle Scholar
Meng  L , Shen  L , Ji  HF .  Impact of infection on risk of Parkinson’s disease: a quantitative assessment of case-control and cohort studies.   J Neurovirol. 2019;25(2):221-228. doi:10.1007/s13365-018-0707-4PubMedGoogle ScholarCrossref
Wijarnpreecha  K , Chesdachai  S , Jaruvongvanich  V , Ungprasert  P .  Hepatitis C virus infection and risk of Parkinson’s disease: a systematic review and meta-analysis.   Eur J Gastroenterol Hepatol. 2018;30(1):9-13. doi:10.1097/MEG.0000000000000991PubMedGoogle ScholarCrossref
Maurizi  CP .  Influenza caused epidemic encephalitis (encephalitis lethargica): the circumstantial evidence and a challenge to the nonbelievers.   Med Hypotheses. 2010;74(5):798-801. doi:10.1016/j.mehy.2009.12.012PubMedGoogle ScholarCrossref
Toovey  S , Jick  SS , Meier  CR .  Parkinson’s disease or Parkinson symptoms following seasonal influenza.   Influenza Other Respir Viruses. 2011;5(5):328-333. doi:10.1111/j.1750-2659.2011.00232.xPubMedGoogle ScholarCrossref
Harris  MA , Tsui  JK , Marion  SA , Shen  H , Teschke  K .  Association of Parkinson’s disease with infections and occupational exposure to possible vectors.   Mov Disord. 2012;27(9):1111-1117. doi:10.1002/mds.25077PubMedGoogle ScholarCrossref
Vlajinac  H , Dzoljic  E , Maksimovic  J , Marinkovic  J , Sipetic  S , Kostic  V .  Infections as a risk factor for Parkinson’s disease: a case-control study.   Int J Neurosci. 2013;123(5):329-332. doi:10.3109/00207454.2012.760560PubMedGoogle ScholarCrossref
Mattock  C , Marmot  M , Stern  G .  Could Parkinson’s disease follow intra-uterine influenza?: a speculative hypothesis.   J Neurol Neurosurg Psychiatry. 1988;51(6):753-756. doi:10.1136/jnnp.51.6.753PubMedGoogle ScholarCrossref
Ebmeier  KP , Calder  SA , Besson  JA .  Psychiatric aspects of Parkinson’s disease.   BMJ. 1989;299(6700):683. doi:10.1136/bmj.299.6700.683PubMedGoogle ScholarCrossref
Liu  B , Chen  H , Fang  F , Tillander  A , Wirdefeldt  K .  Early-life factors and risk of Parkinson’s disease: a register-based cohort study.   PLoS One. 2016;11(4):e0152841. doi:10.1371/journal.pone.0152841PubMedGoogle Scholar
Postuma  RB , Wolfson  C , Rajput  A ,  et al.  Is there seasonal variation in risk of Parkinson’s disease?   Mov Disord. 2007;22(8):1097-1101. doi:10.1002/mds.21272PubMedGoogle ScholarCrossref
Troyer  EA , Kohn  JN , Hong  S .  Are we facing a crashing wave of neuropsychiatric sequelae of COVID-19? neuropsychiatric symptoms and potential immunologic mechanisms.   Brain Behav Immun. 2020;87:34-39. doi:10.1016/j.bbi.2020.04.027PubMedGoogle ScholarCrossref
Christiansen  CF , Heide-Jørgensen  U , Rasmussen  TB ,  et al.  Renin-angiotensin system blockers and adverse outcomes of influenza and pneumonia: a Danish cohort study.   J Am Heart Assoc. 2020;9(19):e017297. doi:10.1161/JAHA.120.017297PubMedGoogle Scholar
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