Innate immunity;

What’s the connection between flu vaccination and lower risk of Alzheimer’s Disease?

FA Manian MD, MPH, , , , , , , , , , , , , , Leave a comment

As far fetched that it may sound, there is growing evidence that flu vaccination is associated with lower risk of being diagnosed with Alzheimer’s Disease (AD).1

The most compelling evidence to date comes from a 2022 retrospective, propensity-matched study involving a nationwide sample of over 2 million U.S. adults ≥ 65 years old.1  This study found a 40% reduction in the risk of incident AD during the 4-year follow-up period when individuals receiving at least 1 dose of flu vaccine were compared to those who did not receive flu vaccination during the study period (number needed to treat-NTT 29.4). 

Despite its limitations, the results of the above study were concordant with those of several smaller studies that found an association between flu vaccination and lower risk of dementia of any cause.1-3  A 2022 meta-analysis also concluded that flu vaccination was associated with significantly lower risk (33%) of dementia among older people. Interestingly, in a study involving veterans, receipt of ≥6 doses of flu vaccines (not fewer) was associated with lower risk of dementia.4

Several hypotheses have been posited to explain the potential beneficial impact of flu vaccination on the risk of dementia, including: 1. Influenza-specific mechanisms, such as mitigation of damage secondary to influenza infection and/or epitopic similarity between influenza proteins and AD pathology; 2. Non-influenza-specific training of the innate immune system; and 3. Non-influenza-specific changes in adaptive immunity via lymphocyte-mediated cross-reactivity.1

So, in addition to its protective effect against severe influenza,5 and its association with lower risk of hospitalization for cardiac disease and stroke and reduction in death due to combined cardiovascular disease events (eg, heart attacks/strokes),  flu vaccination may be protective against AD! Who would have thought that a simple vaccine may have far reaching health benefits?

Bonus Pearl: Did you know that mice infected with non-neurotropic influenza strains have been found to have excessive microglial activation and subsequent alteration of neuronal morphology, particularly in the hippocampus, and that in APP/PS1 transgenic mice, peripheral influenza infection induces persistent elevations of amyloid- (A) plaque burden?1  Intriguing indeed!!!

Liked this post? Download the app on your smart phone and sign up below to catch future pearls right into your inbox, all for free!

Subscribe to Blog via Email

Enter your email address to subscribe to this blog and receive notifications of new posts by email.

References

  1. Bukhbinder AS, Ling Y, Hasan O, et al. Risk of Alzheimer’s disease following influenza vaccination: A claims-based cohort study using propensity score matching. Journal of Alzheimer’s Disease 2022; 88:1061-1074. https://pubmed.ncbi.nlm.nih.gov/26945371/  
  2. Liu JC, Hsu YP, Kao PF, et al. Influenza vaccination reduces dementia risk in chronic kidney disease patients: A population-based cohort study. Medicine (Baltimore) 2016 95 :32868. https://pubmed.ncbi.nlm.nih.gov/26945371/
  3. Wiemken TL, Salas J, Hoft DF, et al. Dementia risk following influenza vaccination in a large veteran cohort. Vaccine 2021;39:5524-5531. https://pubmed.ncbi.nlm.nih.gov/34420785/
  4. Veronese N, Demurtas J, Smith L, et al. Influenza vaccination reduces dementia risk: A systematic review and meta-analysis. Ageing Res Rev 2022;73:101534. https://pubmed.ncbi.nlm.nih.gov/34861456/
  5. Godoy P, Romero A, Soldevila N, et al. Influenza vaccine effectiveness in reducing severe outcomes over six influenza seasons, a case-cae analysis, Spain, 2010/11 to 2015/16.  Euro Surveill 2018;23:1700732. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6208006/
  6. Hosseini S, Michaelsen-Preusse K, Schughart K, et al. Long-term consequences of non-neurotropic H3N2 influenza A virus infection for the progression of Alzheimer’s Disease symptoms. Front. Cell. Neurosci 28 April 2021; https://doi.org/10.3389/fncel.2021.643650 https://www.frontiersin.org/articles/10.3389/fncel.2021.643650/full

Disclosures: The listed questions and answers are solely the responsibility of the author and do not necessarily represent the official views of Mercy Hospital-St. Louis, Massachusetts General Hospital, Harvard Catalyst, Harvard University, their affiliate academic healthcare centers, or its contributors. Although every effort has been made to provide accurate information, the author is far from being perfect. The reader is urged to verify the content of the material with other sources as deemed appropriate and exercise clinical judgment in the interpretation and application of the information provided herein. No responsibility for an adverse outcome or guarantees for a favorable clinical result is assumed by the author. Thank you!

 

What’s the connection between flu vaccination and lower risk of Alzheimer’s Disease?

Are women at higher risk of Covid-19 vaccine-related adverse events?

FA Manian MD, MPH, , , , , , , , , , , , , , , , , , , , , , , , , Leave a comment

Data to date shows a preponderance of Covid-19 vaccine-related adverse events (AEs) among women compared to men. This finding may be due to the generally more robust immunological response to infections and vaccines among women, increased reporting of AEs by women, genetic factors, microbiome differences as well as other factors.1-3

A CDC study involving mRNA vaccines (Pfizer and Moderna) during the 1st month of vaccination roll out in the US, found that nearly 80% of adverse events were reported by women.  The great majority (>90%) of these AEs were not serious and included symptoms such as headache, dizziness and fatigue.1

A JAMA study involving individuals receiving one of the mRNA vaccines found that 94% (Pfizer) and 100% (Moderna) of anaphylaxis events occurred among women. Of note, the median age was ~40 years  with the majority of anaphylaxis events were reported after the first dose. 2

Higher incidence of AEs following Covid-19 vaccination is not surprising and may be explained biologically. Women typically have a more robust immune response to infections and vaccination, both at the level of innate and adaptive immunity with higher antibody responses.  

These findings may be in part due to hormones such as estrogen which is known to enhance differentiation of dendritic cells and proinflammatory cytokine production. Other proposed mechanisms include differences in microbiome between sexes and sex-based genetic influences on humoral immune profile with the X chromosome expressing 10 times more genes than the Y chromosome, including genes that influence immunity.3

Bonus Pearl: Did you know that anaphylactic reaction to the mRNA Covid-19 vaccines is extremely rare, occurring in only 2-5 cases/ million!2

Liked this post? Download the app on your smart phone and sign up below to catch future pearls right into your inbox, all for free!

Subscribe to Blog via Email

Enter your email address to subscribe to this blog and receive notifications of new posts by email.

References

  1. Gee J, Marquez P, Su J, et al. First month of Covid-19 vaccine safety monitoring—United States, December 14, 2020—January 13, 2021. MMWR 2021;70:283-88. https://www.cdc.gov/mmwr/volumes/70/wr/mm7008e3.htm
  2. Shimabukuro TT, Cole M, Su JR. Reports of anaphylaxis after receipt of mRNA Covid-19 vaccines in the US—December 14, 2020-January 18, 2021. JAMA 20201;325:1101-1102. https://jamanetwork.com/journals/jama/fullarticle/2776557
  3. Fischinger S, Boudreau CM, Butler AL, et al. Sex differences in vaccine-induced humoral immunity. Semin Immunopath 2019;41:239-49. https://pubmed.ncbi.nlm.nih.gov/30547182/

Disclosures: The listed questions and answers are solely the responsibility of the author and do not necessarily represent the official views of Mercy Hospital-St. Louis or its affiliate healthcare centers, Mass General Hospital, Harvard Medical School or its affiliated institutions. Although every effort has been made to provide accurate information, the author is far from being perfect. The reader is urged to verify the content of the material with other sources as deemed appropriate and exercise clinical judgment in the interpretation and application of the information provided herein. No responsibility for an adverse outcome or guarantees for a favorable clinical result is assumed by the author. Thank you!

Are women at higher risk of Covid-19 vaccine-related adverse events?

Do statins have a role in treating novel Coronavirus infection, COVID-19?

FA Manian MD, MPH, , , , , , , , , , , , , , , , , , , , , , , , Leave a comment

There is currently no firm clinical evidence that statins improve the outcome of COVID-19. However, there are some theoretical reasons for believing that statins may have a role in the treatment of COVID-19.  That’s because beyond their cholesterol lowering action, statins may also have clinically relevant anti-inflammatory and antiviral (pleotropic) properties.  

Anti-inflammatory: Anti-inflammatory effect of statins is well known and is thought to occur through a variety of molecular pathways of the innate and adaptive immune systems as well as attenuation of several circulating proinflammatory cytokines.1 Although observational studies have suggested that statins lower hospitalization and mortality among outpatients hospitalized with infection, pneumonia or sepsis, several randomized controlled trials (RCTs) have failed to show any mortality benefit among ICU patients with sepsis and ARDS treated with statins.2

In contrast, an RCT involving patients with sepsis (majority with pneumonia, mean CRP 195 mg/dL) reported significant reduction in progression to severe sepsis among statin-naïve patients  placed on atorvastatin 40 mg/day at the time of hospitalization.3 So, perhaps timing of statin therapy before florid sepsis and ARDS is an important factor.  

Some have suggested that statins may decrease the fatality rate of a related Coronavirus, Middle East Respiratory Syndrome (MERS) virus, by blunting exuberant inflammatory response that may result in a fatal outcome. 4

Antiviral: Statins may also have antiviral properties, including activity against influenza, hepatitis C virus, Zika and dengue viruses.2,5 Whether statins have activity against coronaviruses such as the agent of COVID-19 is unclear at this time.

It’s interesting to note that cholesterol may have an important role in the membrane attachment, fusion and replication of many enveloped viruses, including influenza.5 Covid-19 is also an enveloped virus.

So what do we do? Based on the current data, it makes sense to continue statins in patients who have known clinical indications for their use and no obvious contraindications because of COVID-19 (eg. rhabdomyolysis).6 As for statin-naïve patients, particularly those in early stages of sepsis and increased risk of cardiovascular events, benefit may outweigh the risk.  Only proper clinical studies will give us more definitive answers.

Bonus Pearl: Did you know that lipids make up a major component of the envelope in enveloped viruses and that cholesterol makes up nearly one-half of total lipid and over 10% the total mass of influenza viruses?

Liked this post? Download the app on your smart phone and sign up below to catch future pearls right into your inbox, all for free!

Subscribe to Blog via Email

Enter your email address to subscribe to this blog and receive notifications of new posts by email.

References

  1. Tousoulis D, Psarros C, Demosthenous M, et al. Innate and adaptive inflammation as a therapeutic target in vascular diseae: The emerging role of statins. J Am Coll Cardiol 2014;63:2491-2502. https://www.sciencedirect.com/science/article/pii/S0735109714011553?via%3Dihub
  2. Fedson DS. Treating the host response to emerging virus diseases: lessons learned from sepsis, pneumonia, influenza and Ebola. Ann Transl Med 2016;4:421. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5124618/pdf/atm-04-21-421.pdf
  3. Patel JM, Snaith C, Thickette DR. Randomized double-blind placebo-controlled trial of 40 mg/day of atorvastatin in reducing the severity of sepsis in ward patients (ASEPSIS Trial) Critical Care 2012;16:R231. https://ccforum.biomedcentral.com/track/pdf/10.1186/cc11895
  4. Espano E, Nam JH, Song EJ, et al. Lipophilic statins inhibit Zika virus production in Vero cells. Scientific Reports 2019;9:11461. https://www.nature.com/articles/s41598-019-47956-1
  5. Sun X, Whittaker GR. Role for influenza virus envelope cholesterol in virus entry and infection. J Virol 2003;77:12543-12551. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC262566/
  6. Virani SS. Is there a role for statin therapy in acute viral infections. Am Coll Cardiol March 18, 2020. https://www.acc.org/latest-in-cardiology/articles/2020/03/18/15/09/is-there-a-role-for-statin-therapy-in-acute-viral-infections-covid-19

Disclosures: The listed questions and answers are solely the responsibility of the author and do not necessarily represent the official views of Massachusetts General Hospital, Harvard Catalyst, Harvard University, its affiliate academic healthcare centers, or its contributors. Although every effort has been made to provide accurate information, the author is far from being perfect. The reader is urged to verify the content of the material with other sources as deemed appropriate and exercise clinical judgment in the interpretation and application of the information provided herein. No responsibility for an adverse outcome or guarantees for a favorable clinical result is assumed by the author. Thank you!

Do statins have a role in treating novel Coronavirus infection, COVID-19?

Are NSAIDS contraindicated in patients with 2019 novel Coronavirus infection (Covid-19)?

FA Manian MD, MPH, , , , , , , , , , , , , , , , , 1 Comment

Despite recent internet reports of the association of non-steroidal anti-inflammatory drugs (NSAIDs) with worsening symptoms among patients with Covid-19 (1), firm clinical evidence to support such claims is currently lacking. However, there are some theoretical reasons why it may still be best to avoid NSAIDs in this condition due to their potential adverse impact on the innate and adaptive immune responses as well as their antipyretic properties (2-9).

 
Blunting of the innate immune response: Certain NSAIDs (eg, ibuprofen, naproxen and celecoxib) inhibit cyclooxygenase enzyme-2 (COX-2) and impair production of several pro-inflammatory cytokines important in fighting infections, such as tumor necrosis factor, interleukin 1 and 6, as well as interferon, an antiviral cytokine (2,6,8). COX-2 has been shown to be important in controlling viral replication in influenza (4). Ibuprofen has been associated with inhibitory effects on a variety of polymorphonuclear functions, including chemotaxis (2).

 
Impact on adaptive immune response: COX-2 inhibition may be associated with impaired neutralizing antibody production (3,4,8). Potential mechanisms include modulation of cytokine expression, nitric-oxide production, and antigen processing/presentation and T lymphocyte activation (3,8).

 
Antipyretic effect: NSAIDs are often given for treatment of fever which is an evolutionary host response to infection. A meta-analysis of animal studies evaluating the impact of antipyretics (including aspirin, NSAIDs, and acetaminophen) in influenza found lower survival in animals treated with antipyretics (9). Longer duration of viral shedding has also been associated with the use of aspirin or acetaminophen in rhinovirus infection (9).

 
Formal epidemiologic and experimental studies are sorely needed to evaluate the safety of NSAIDS in Covid-19.  

 

Liked this post? Download the app on your smart phone and sign up below to catch future pearls right into your inbox, all for free!

Subscribe to Blog via Email

Enter your email address to subscribe to this blog and receive notifications of new posts by email.

 

 

References
1. Kolata G. Is ibuprofen really risky for Coronavirus patients? NY Times, March 17, 2020. https://www.nytimes.com/2020/03/17/health/coronavirus-ibuprofen.html
2. Graham NMH, Burrell CJ, Douglas RM, et al. Adverse effects of aspirin, acetaminophen and ibuprofen on immune function, viral shedding, and clinical status in rhinovirus-infected volunteers. J Infect Dis 1990;162:1277-1282. https://academic.oup.com/jid/article/162/6/1277/918184
3. Culbreth MJ, Biryunkov S, Shoe JL, et al. The use of analgesics during vaccination with a live attenuated Yersinia pestis vaccine alters the resulting immune response in mice. Vaccines 2019;7, 205; doi:10.3390/vaccines7040205 https://www.mdpi.com/2076-393X/7/4/205
4. Ramos I, Fernandez-Sesma A. Modulating the innate immune response to influenza A virus:potential therapeutic use of anti-inflammatory drugs. Frontiers in Immunology. July 2015. Volume 6. Article 361. https://www.ncbi.nlm.nih.gov/pubmed/26257731
5. Falup-Pecurariu O, Man SC, Neamtu ML, et al. Effects of prophylactic ibuprofen and paracetamol administration on the immunogenicity and reactogenicity of the 10-valent pneumococcal non-typeable Haemophilus influenzae protein D conjugated vaccine(PHID-CV) co-administered with DTPa-combined vaccines in children:An open-label, randomized, controlled, non-inferiority trial. Human Vaccines & Immunotherapeutics 2017;13: 649-660. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5360152/
6. Housby JN, Cahill CM, Chu B, et al. Non-steroidal anti-inflammatory drugs inhibit the expression of cytokines and induce HSP70 in human monocytes. Cytokine 1999;11:347-58. https://www.ncbi.nlm.nih.gov/pubmed/30186359
7. Agarwal D, Schmader KE, Kossenkov AV, et al. Immune response to influenza vaccination in the elderly is altered by chronic medication use. Immunity & Ageing 2018;15:19. https://www.ncbi.nlm.nih.gov/pubmed/30186359
8. Bancos S, Bernard MP, Topham DJ, et al. Ibuprofen and other widely used non-steroidal anti-inflammatory drugs inhibit antibody production in human cells. Cell Immunol 2009;258:18-28. https://www.ncbi.nlm.nih.gov/pubmed/19345936
9. Eyers S, Weatherall M, Shirtcliffe P, et al. The effect on mortality of antipyretics in the treatment of influenza infection: systematic review and meta-analysis. J R Soc Med 2010;103:403-11. https://www.ncbi.nlm.nih.gov/pubmed/20929891

 

Disclosures: The listed questions and answers are solely the responsibility of the author and do not necessarily represent the official views of Massachusetts General Hospital, Harvard Catalyst, Harvard University, its affiliate academic healthcare centers, or its contributors. Although every effort has been made to provide accurate information, the author is far from being perfect. The reader is urged to verify the content of the material with other sources as deemed appropriate and exercise clinical judgment in the interpretation and application of the information provided herein. No responsibility for an adverse outcome or guarantees for a favorable clinical result is assumed by the author. Thank you!

Are NSAIDS contraindicated in patients with 2019 novel Coronavirus infection (Covid-19)?