The influence of influenza

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The potential long-term consequences of viral infections is not a popular topic for a research blog in the middle of a pandemic (and yes, we are still in the middle of it!), but there is a recent Parkinson’s-related report that is worth discussing.

Researchers have recently looked at medical records dating back several decades and noticed something interesting about influenza infections: They are associated with diagnoses of Parkinson’s more than 10 years after infection.

NOTE: The data does not indicate a causal link, just an association.

In today’s post, we will discuss what influenza is, how it has previously been associated with PD, what the new report found, and we will speculate on potential mechanisms by which viral infections could be playing a role in Parkinson’s.

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photo_66943_landscape_650x433

1918 Spanish flu. Source: Chronicle

Between January 1918 and December 1920, there were two outbreaks of an influenza virus during an event that became known as the 1918 flu pandemic.

Approximately 500 million people across the globe were infected by the H1N1 influenza virus, and this resulted in 50 to 100 million deaths (approximately 3-5% of the world’s population). Given that it occurred during World War 1, censors limited the media coverage of the pandemic in many countries in order to maintain morale.

The Spanish media were not censored, however, and this is why the 1918 pandemic is often referred to as the ‘Spanish flu’.

At the same time that H1N1 was causing havoc, a Romanian born neurologist named Constantin von Economo reported a number of cases involving unusual symptoms. The collection of symptoms was eventually given a name: encephalitis lethargica (EL).

Economo

Constantin von Economo. Source: Wikipedia

This disease left victims in a statue-like condition, speechless and motionless. By 1926, EL had spread around the world, with nearly five million people being affected.

vonecomo-parkinson

An individual with encephalitis lethargica. Source: Baillement

Was influenza causing EL?

Historically, it was believed that EL was caused by the influenza virus from the 1918 Spanish influenza pandemic. This was largely due to a temporal association (things happening at approximately the same time) and the finding of influenza antigens in some of the suffers of EL (Click here to read more about this).

More recently, however, postmortem analysis of the brains of EL patients found an absence of influenza RNA (Click here to read more about this), which has led many researchers to simply reject the association between influenza and EL. The evidence supporting this rejection, however, has also been questioned (Click here to read more about this), leaving the question of an association between influenza and EL still open for debate.

I think it’s fair to say that we genuinely do not know what caused EL. Whether it was influenza or not is still be undecided.

Very interesting, but can you just explain exactly what influenza is?

Influenza is a single-stranded, RNA virus of the orthomyxovirus family of viruses.

3D_Influenza_transparent_key_pieslice_lrg

A schematic of the influenza virus. Source: CDC

It is the virus that causes ‘the flu’ – (runny nose, sore throat, coughing, and fatigue) – with the symptom arising two days after exposure and lasting for about a week. In humans, there are three types of influenza viruses, called Type A, Type B, and Type C. Type A are the most virulent in humans. The influenza virus behind both of the outbreaks in the 1918 pandemic was a Type A.

influenzaha-na

Schematic of Influenza virus. Source: Bcm

As the image above indicates, the influenza virus has a rounded shape, with “HA” (hemagglutinin) and “NA” (neuraminidases) proteins on the outer surface of the virus. The HA protein allows the virus to stick to the outer membrane of a cell. The virus can then infect the host cell and start the process of reproduction – making more copies of itself. The NA protein is required for the virus to exit the host cell and go on to infect other cells. Different influenza viruses have different combinations of hemagglutinin and neuraminidase proteins, hence the numbering. For example, the Type A virus that caused the outbreaks in the 1918 pandemic was called H1N1.

Inside the influenza virus, there are there are eight pieces (segments) of RNA, hence the fact that influenza is an RNA virus. Some viruses have DNA while others have RNA. The 8 segments of RNA provide the information that is required for making new copies of the virus. Each of these segments provides the instructions for making one or more proteins of the virus (eg. segment 4 contains the instructions to make the HA protein).

martinez-influenza-virus

The 8 segments of RNA in influenza. Source: URMC

The Influenza virus is one of the most changeable viruses we are aware of, which makes it such a tricky beast to deal with. Influenza uses two techniques to change over time. They are called shift and drift.

Shifting is an sudden change in the virus, which produces a completely new combination of the HA and NA proteins. Virus shift can take place when a person or animal is infected with two different subtypes of influenza. When new viral particles are generated inside the cell, there is a mix of both subtypes of virus which gives rise to an all new type of virus.

flu-reassortment-320-240-20131210133600

An example of viral shift. Source: Bcm

Drifting is the process of random genetic mutation. Gradual, continuous, spontaneous changes that occur when the virus makes small “mistakes” during the replication of its RNA. These mistakes can results in a slight difference in the HA or NA proteins, and although those changes are small, they can be significant enough that the human immune system will no longer recognise and attack the virus. This is why you can repeatedly get the flu and why flu vaccines must be administered each year to combat new forms of circulating influenza virus.

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RECAP #1:  Influenza is a virus that is associated with seasonal infections. It was the cause of the 1918 pandemic which caused millions of deaths and severe economic consequences.

A Parkinson’s-like condition called encephalitis lethargica has been associated with influenza, but the evidence supporting this link has not been conclusive.

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Got it. So we don’t know if encephalitis lethargica is caused by influenza then. What about Parkinson’s? Are there any links to influenza?

Funny you should ask.

Recently, this report was published:

Title: Long-term Risk of Parkinson Disease Following Influenza and Other Infections.
Authors: Cocoros NM, Svensson E, Szépligeti SK, Vestergaard SV, Szentkúti P, Thomsen RW, Borghammer P, Sørensen HT, Henderson VW.
Journal: JAMA Neurol. 2021 Oct 25. Online ahead of print.
PMID: 34694344

In this study, the researchers collected medical records data from 1977 to 2016 from the Danish National Patient Registry. They wanted to “examine whether prior influenza and other infections are associated with Parkinson disease more than 10 years after infection”.

To do this, they performed a case-control study.

What is a case-control study?

A case–control study is a type of observational study in which two existing groups differing in outcome are identified and compared on the basis of some supposed causal attribute.

Source: Deakin

In a case-control study patients who have developed a particular medical condition are identified and their past history is examined for exposure to potentially influential factors in the development of their condition. These are compared with that of a control group who do not have the disease. This type of analysis permits estimation of odds ratios (which are measures of association, rather than risk or causation).

Got it. So what did the researchers do next?

The researchers identified all of the Parkinson’s diagnoses that occurred between January 1, 2000, and December 31, 2016. Next, they gathered information about infections from the medical records that occurred between 1977 and 2016. They then categorised the infections by time from infection to Parkinson’s diagnosis.

To help define the ‘infection’ as influenza, they restricted the “influenza infections” to the months of peak influenza activity.

And once they had done this, they pulled all of their data together and analysed it.

What they found was rather intriguing.

What did they find?

A total of 10 271 individuals with Parkinson were identified, and their medical record data was compared with a control group of 51 355 individuals.

When the investigators looked at influenza infections, they found that a diagnosis of influenza at any time during a particular year was associated with a diagnosis of Parkinson’s more than 10 years later. The odds ratio for this was 1.73 (95% confidence interval of 1.11-2.71).

What does that mean? What is an odds ratio?

An odds ratio is a statistic that compares the relative odds of the occurrence of the outcome of particular interest (in our case: Parkinson’s), given exposure to a particular variable of interest (in this situation: influenza). It is a statistic that quantifies the strength of the association between two events.

Using the example of today’s post, an odds ratio of 1.0 would mean that exposure to influenza does not affect the odds of being diagnosed with Parkinson’s. A number below 1.0 (such as 0.35 equals) suggests that exposure to influenza is associated with lower odds of being diagnosed with Parkinson’s.

In the current study, the researchers found that the odds ratio for this was 1.73 (95% confidence interval of 1.11-2.71).

And what does the 95% confidence interval part mean?

A confidence interval (CI) is used by statisticians to estimate the precision of the odds ratio. A large CI indicates a low level of precision of the odds ratio, while a small CI suggests much higher precision. The 95% part refers to the fact that 95% of the data falls within the stated range (in this case 1.11 to 2.71). The remaining 5% of the data can be considered outliers.

In the case of today’s post, a 95% confidence interval of 1.11-2.71 is reasonably ok. If the figures were 1.03-15.8, the precision would be rather low.

Got it. So influenza exposure was associated with a diagnosis of Parkinson’s more than 10 years later. What else did the researchers find?

When they restricted their analysis to influenza exposure during the months of highest influenza activity, the odds ratio shifted to 1.52 with a 95% confidence interval of 0.80-2.89.

But of particular interest to this discussion: When the investigators conducted the analysis on other types of infections, there was no
evidence of an association with a diagnosis of Parkinson’s more than 10 years later (odds ration of 1.04 with a 95% confidence interval of 0.98-1.10).

They did find increased odds of a Parkinson’s diagnosis within 5 years of of an infection for several specific types of infections, but these lost their association beyond 10 years, which suggest these shorter-term associations probably had no causal role.

Does this mean that influenza is causing Parkinson’s?!?

While the data are very interesting, we cannot assume a causal role for influenza in Parkinson’s based on these results.

And it is important to appreciate that the researchers who conducted the study are very quick to point out that “these observational data suggest a link between influenza and Parkinson disease but do not demonstrate causality“.

Ok. But have researcher ever investigated an association between Parkinson’s and influenza before?

Good question.

And yes they have:

flu1Title: Parkinson’s disease or Parkinson symptoms following seasonal influenza.
Authors: Toovey S, Jick SS, Meier CR.
Journal: Influenza Other Respir Viruses. 2011 Sep;5(5):328-33.
PMID: 21668692            (This article is OPEN ACCESS if you would like to read it)

In this first study, the researcher used the UK‐based General Practice Research Database to perform a case–control analysis. They identified individual cases who had developed an ‘incident diagnosis’ of Parkinson’s or Parkinson’s like symptoms between 1994 and March 2007. For each of those case files identified, they matched them with at least four age matched control case files for comparative sake.

Their analysis found that the risk of developing Parkinson’s disease was not associated with previous influenza infections. BUT, they did find that influenza was associated with Parkinson’s‐like symptoms such as tremor, particularly in the month after an infection.

But this situation is slightly confused by a second research report that was published one year after this first study:

occupationJournal: Association of Parkinson’s disease with infections and occupational exposure to possible vectors.
Authors: Harris MA, Tsui JK, Marion SA, Shen H, Teschke K.
Journal: Movement Disorder. 2012 Aug;27(9):1111-7.
PMID: 22753266

This second study reported that there is actually an association between Parkinson’s and influenza.

This investigation was also a case-control study, but it was based in British Columbia, Canada. The researchers recruited 403 individuals detected by their use of antiparkinsonian medications and matched them with 405 control subjects selected from the universal health insurance plan. Severe influenza was associated with Parkinson’s at an odds ratio of 2.01 and the range of the odds was 1.16-3.48.

Interestingly, the effect was reduced when the reports of infection were restricted to those occurring within 10 years before diagnosis.

 

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RECAP #2:  Researchers analysed Danish medical records data from 1977 to 2016 to determine if there is an association between influenza and a later diagnosis of Parkinson’s.

They found a diagnosis of influenza at any time during a particular year was associated with a diagnosis of Parkinson’s more than 10 years later.

Previous epidemiological data is conflicted on associations between Parkinson’s and influenza.

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Is there any preclinical research suggesting that influenza could be involved in Parkinson’s?

Research groups have looked into this and published their reports on this topic.

In 2009, this study was published:

PNAS

Title: Highly pathogenic H5N1 influenza virus can enter the central nervous system and induce neuroinflammation and neurodegeneration.
Author: Jang H, Boltz D, Sturm-Ramirez K, Shepherd KR, Jiao Y, Webster R, Smeyne RJ.
Journal: Proc Natl Acad Sci U S A. 2009 Aug 18;106(33):14063-8.
PMID: 19667183                 (This article is OPEN ACCESS if you would like to read it)

In this study, the researchers injected the highly infectious A/Vietnam/1203/04 (H5N1) influenza virus into mice, and found that the virus progressed from the periphery (outside the brain) into the brain itself, where it induced Parkinson’s-like symptoms.

The virus also caused a significant increase in the accumulation of the Parkinson’s-associated protein alpha synuclein. In addition, they witnessed the loss of dopamine neurons in the midbrain of the mice at 60 days after the infection – that cell loss resembling what is observed in the brains of people with Parkinson’s.

Naturally this got the researchers rather excited.

In a follow up study on H5N1, however, these same researchers found that the Parkinson’s-like symptoms that they observed were actually only temporary:

JNS

Title: Inflammatory effects of highly pathogenic H5N1 influenza virus infection in the CNS of mice.
Authors: Jang H, Boltz D, McClaren J, Pani AK, Smeyne M, Korff A, Webster R, Smeyne RJ.
Journal: Journal for Neuroscience, 2012 Feb 1;32(5):1545-59.
PMID: 22302798                   (This article is OPEN ACCESS if you would like to read it)

In this study, the researchers repeated their 2009 study and had a closer look at what was happening to the dopamine neurons that were disappearing at 60 days post infection with the virus. When they looked at mice at 90 days post infection, they found that the number of dopamine neurons had returned to their normal number. This pattern was also observed in a region of the brain called the striatum, where the dopamine neurons release their dopamine. The levels of dopamine dropped soon after infection, but rose back to normal by 90 days post infection.

Huh??? How does that work???

The results suggest that the dopamine neurons that were infected by the virus simply stopped producing dopamine while they dealt with the viral infection. Once the crisis was over, the dopamine neurons went back to life as normal. And because the researcher use chemicals in the production of dopamine to identify the dopamine neurons, they mistakenly thought that the cells had died when they could not see those chemicals.

One interesting observation from the study was that H5N1 infection in mice induced a long-lasting inflammatory response in brain. The resident helper cells, called microglia, became activated by the infection, but remained active long after the dopamine neurons returned to normal service. The investigators speculated as to whether this activation may be a contributing factor in the development of neurodegenerative disorders.

And this is an interesting idea.

In a follow up study, they investigated this further by looking another influenza virus that doesn’t actually infect cells in the brain:

PLOS

Title: Induction of microglia activation after infection with the non-neurotropic A/CA/04/2009 H1N1 influenza virus.
Author: Sadasivan S, Zanin M, O’Brien K, Schultz-Cherry S, Smeyne RJ.
Journal: PLoS One. 2015 Apr 10;10(4):e0124047.
PMID: 25861024                (This article is OPEN ACCESS if you would like to read it)

In this study, a different type of influenza (H1N1) was tested, and while it did not infect the brain, it did cause the microglia cells to flare up and become activated. And again, this activation was sustained for a long period after the infection (at least 90 days).

This is a really interesting finding and relates to the idea of a “double hit” theory of Parkinson’s, in which the virus doesn’t necessarily cause Parkinson’s but may play a supplemental role, grabbing the attention of the immune system while some other toxic agent is also attacking the body. Or perhaps simply weakening the immune system by forcing it to fight on multiple fronts. Alone the two would not cause as much damage, but in combination they could deal a terrible blow.

If one has Parkinson’s, are you more vulnerable to viruses like influenza?

We don’t really know, so obviously caution should be taken.

But there is some data suggesting that some Parkinson’s-associated genetic variants could reduce the impact of being infected with a virus like influenza.

What?!?

In 2019, this research report was published:

Title: Glucosylceramidase Maintains Influenza Virus Infection by Regulating Endocytosis.
Authors: Drews K, Calgi MP, Harrison WC, Drews CM, Costa-Pinheiro P, Shaw JJP, Jobe KA, Nelson EA, Han JD, Fox T, White JM, Kester M.
Journal: J Virol. 2019 May 29;93(12):e00017-19.
PMID: 30918081             (This report is OPEN ACCESS if you would like to read it)

In this study, the researchers found that deletion of the Parkinson’s-associated gene GBA (which produces the enzyme glucocerebrosidase – also known as GCase) led to reduced influenza virus infections of different kinds of cells grown in culture:

Normal cells vs GBA knockout (KO). Source: PMC

Specifically, their studies indicated that the reduction in infection correlated with impaired influenza virus trafficking to late endosomes/lysosomes. To learn more about the nature of GBA and GCase in Parkinson’s – click here to a previous SoPD post on this topic.

Curiously, this effect was not limited to just influenza: The researchers also found a similar effect when they infected GBA knockout cells with Ebola virus (yes, that Ebola!). But for other viruses (such as the measles virus), the deletion of GBA resulted in little difference compared to normal cells.

The biology behind this research needs to be better understood, so no one with Parkinson’s should suddenly feel invincible against viral infections (please take precautions – particularly with COVID19! – wear a mask and practice social distancing), but it is an interesting observation.

So what does it all mean?

As the viral pandemic known as COVID19 continues to cause hardship around the world, new research has been published that suggests influenza infections are associated with higher odds of a Parkinson’s diagnosis ten years later. While this data does not infer causation, it could be seen as further support for a role of environmental stressors in the development of the condition – possibly as part of a dual hit approach.

The exact nature of what is causing most cases of Parkinson’s is unknown, and the variability in onset, symptoms and progression between cases suggests an increased likelihood of different causal factors. Environmental stressors like viral infections could be playing a role in the development of the condition, but this obviously requires further investigation.

 

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The banner for today’s post was sourced from cdc

3 thoughts on “The influence of influenza

  1. Very interesting. Of course the argument of association relies on an official diagnosis being recorded. Personally, I suffered the worst flu symptoms with a week long fever without ever taking myself to the doctor and therefore this would not have been recorded. This was 9 years ago. I was diagnosed with Parkinson’s 7 years ago and have often considered my flu as being something of a trigger.

    Like

  2. Suggestion for a new post: The Influence of Bacterial Infections.

    I suggest this as I had Rheumatic Fever at the age of 7. I was given penicillin daily until the age of 18. I was diagnosed with PD at the age of 58.

    Hmm, maybe make that: The Influence of Bacterial Infections or Long-term Treatment with Antibiotics.

    Like

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