While viral infections are well known to be potential antecedents and triggers for chronic diseases in the GI tract as well as inducers of some cancers, the research implicating infections as risk factors for other types of chronic diseases remains controversial. From the association between infections and autoimmune diseases¹ to some high profile examples of diseases associated with rare viruses that did not pan out,² the research has been tantalizing but ultimately not fully conclusive. Now, two new studies add to the evidence that common viral infections may serve as risk factors and perhaps precipitating events in the development of neurodegenerative diseases.

There has been significant investigation into viral infections as precipitators of neurological conditions³ but little conclusive evidence. Functional medicine practitioners will recognize Dr. Leo Galland’s concepts of triggers as discrete entities or events that provoke disease or its symptoms and antecedents as factors that predispose to illness, and that viral infections are likely far more common in the etiology of chronic disease than is currently recognized. The ongoing COVID-19 pandemic is reacquainting many in conventional medicine with this concept as the prevalence of post-acute sequalae of SARS-CoV-2 infection (PASC) grows. The recent work suggests that common infections may be critical events in the development of Parkinson’s disease (PD) and multiple sclerosis (MS).

Infectious Mononucleosis and Multiple Sclerosis

One new study published in JAMA Network Open examined the association between infectious mononucleosis (IM) in childhood and adolescence and risk for subsequent MS diagnosis.⁴ The population-based cohort study of nearly 2.5 million individuals born between 1958 and 1994 in Sweden looked at how pre-adult IM, a symptomatic infection caused by the Epstein-Barr virus (EBV), impacted risk of MS.

Adjusting for shared familial factors, the study found that having been diagnosed with mono during childhood (birth to ten years old) was associated with a 2.87 times higher relative risk of MS (CI, 1.44 to 5.74), while the risk was 3.19 times higher among those who had the infection during adolescence (11-19 years old; CI, 2.29 to 4.46). The authors note that the risk for later MS diagnosis was highest among children who had mono between the ages of 11 and 15 years, a time period in which puberty typically occurs. The risk of developing MS was also elevated for people who had mono in young adulthood (20-24 years old), but this association was no longer significant after controlling for shared familial factors (HR, 1.51; CI, 0.82 to 2.76).⁴

Influenza and Parkinson’s Disease

Another new study, a case-control published in JAMA Neurology, looked at how influenza and other common infections impacted later risk of developing PD.⁵ Using data from the Danish patient registry, researchers looked at 10,271 subjects diagnosed with PD during a 17-year period from 2000-2016 as well as controls without PD. They collected data on influenza diagnoses from inpatient and outpatient hospital clinics from 1977-2016 and 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. They used these remote time points hypothesizing that influenza infection would be unlikely to trigger immediate PD but more likely to instead start a rather long “run-up” to PD. There is often a decades-long preclinical phase before patients develop typical signs of PD, as it seems to take the death of an estimated 70-80% of neurons in the substantia nigra pars compacta before frank dysfunction becomes evident.

The researchers found that for influenza infections that occurred more than 10 years before PD onset, the likelihood of a diagnosis for the infected compared with the unexposed was increased by 73% (OR = 1.73; CI, 1.11 – 2.71), and for cases diagnosed more than 15 years after infection, the adjusted odds ratio was 1.91 (CI, 1.14 – 3.19). The researchers also looked at associations with several other types of infection but did not see the same trend over time. Some infections, for example, gastrointestinal infections and septicemia, were associated with PD within five years, but most of these relationships disappeared by more than 10 years, which the researchers surmised did not indicate a meaningful association.⁵

Potential Mechanisms

So how might common, symptomatic viral infection lead to the development of neurological diseases years later? Based on the time course of these associations, it is not entirely clear whether the infections may be acting as triggers that cause a cascade of events that in time lead to disease or as antecedents that instead change the terrain to make subsequent triggers more likely to cause disease. The authors of the PD study suggest that influenza infection may be a primer or an initial hit to the system, perhaps setting people up to develop PD. Perhaps the influenza virus gets into the central nervous system, resulting in neuroinflammation, or cytokines generated in response to the infection might damage the sensitive dopamine-producing cells of the substantia nigra.

Regarding IM and MS, one of the interesting issues is that EBV is nearly ubiquitous, but only a small proportion of those infected with EBV show symptoms of mono. Symptomatic disease tends to be more common and pernicious the later in life that a patient experiences it. Perhaps there is something systematically different about those who experience IM versus those who don’t that also makes them more likely to get MS? Or maybe the infection itself is the culprit, as the authors suggest that the more severe infections during childhood make it more likely that the virus causes sufficiently serious inflammation in the brain, triggering the immune system to attack myelin. In any event, childhood and adolescence seem to be a critical period for this effect, as the researchers found that after age 15, the risk diminished with increasing age at IM until it was almost eliminated for IM by age 25 years, despite the fact that those later infections are likely to be more deleterious.

Conclusion

The COVID-19 pandemic should be a reminder to us all that viral infections can cause serious collateral damage, sometimes in the form of post-acute syndromes but also potentially as re-awakenings of latent viruses later in life (e.g., shingles) and potentially as remote triggers or even antecedents of later diseases, including neurodegenerative diseases. Some experts are currently concerned that a potential surge in cases of PD or other neurological or autoimmune conditions may be on tap in the next few decades, as SARS-CoV-2 infection may set the stage for ongoing dysfunctional physiological processes. This may become an important consideration in primary care practice in the near future as clinicians grapple with the long-term effects of the pandemic.

References

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2. Mikovits JA, Lombardi VC, Pfost MA, Hagen KS, Ruscetti FW. Detection of an infectious retrovirus, XMRV, in blood cells of patients with chronic fatigue syndrome. Virulence. 2010;1(5):386-390. doi:4161/viru.1.5.12486
3. Zhou L, Miranda-Saksena M, Saksena NK. Viruses and neurodegeneration. Virol J. 2013;10:172. doi:1186/1743-422X-10-172
4. Xu Y, Hiyoshi A, Smith KA, et al. Association of infectious mononucleosis in childhood and adolescence with risk for a subsequent multiple sclerosis diagnosis among siblings. JAMA Netw Open. 2021;4(10):e2124932. doi:1001/jamanetworkopen.2021.24932
5. Cocoros NM, Svensson E, Szépligeti SK, et al. Long-term risk of Parkinson disease following influenza and other infections. JAMA Neurol. Published online October 25, 2021. doi:1001/jamaneurol.2021.3895