Long-term effects of

CMV in the elderly

By Adriaensen Wim

Department of Public Health and Primary Care, KU Leuven & UCL, Belgium

falling in for Prof. Catharina Matheï

Cytomegalovirus

Human Herpes Virus 5 (HHV-5)

Double stranded DNA enveloped herpesvirus

BELFRAIL serology

BELFRAIL – BFc80+

prospective, observational, population-based cohort study of community-dwelling subjects

total of 567 subjects (63% women) with a mean age of 85 years (range 80 - 102) were included between November 2, 2008 and September 15, 2009

29 GP centres recorded background variables and medical history and performed a detailed anamnesis and clinical examination

The CRA performed an extensive examination including questionnaires and technical examinations

BELFRAIL – BFc80+

High burden of comorbidity

Low number of institutionalized

CMV prevalence and determinants

Routinely diagnosed by the detection of anti-CMV IgG & IgM antibodies.

Worldwide high prevalence rates between 40-100% BELFRAIL: 74% Omsk region: 90-95%

“Cytomegalovirus infection in Omsk region. Dolgikh et al. 2008 Zh Mikrobiol Epidemiol Immunobiol.”

Depending on socio-economic status, gender and age.

Generally lower in developed countries, due to improved hygiene in these countries.

Natural History

CMV is transmitted from person to person via close contact with an individual who is excreting the virus.

It can be spread through the placenta, blood transfusions, organ transplantation, and breast milk.

It can also be spread through sexual transmission.

Natural History

Persistent infections: those in which the virus is not cleared but remains in specific cells of infected individuals. Latent in the body Mainly in myeloid lineage and monocytes, epithelial cells.

Involve stages of both silent and productive infection without rapidly killing or even producing excessive damage of the host cells.

Might reactivate after an superinfection, periods of stress, immunodeficiency, etc. Virions appear in saliva, urine? IgM?

No real chronic infection, as a chronic infection is characterized by the continued presence of infectious virus following the primary infection and may include chronic or recurrent disease.

Known consequences of Cytomegalovirus

Usually asymptomatic in healthy people

Dangerous in:

Pregnant mothers and newborns

Immunocompromised situations HIV patients Transplantation

CMV really innocent in healthy persons?

Likewise many other infectious agents, in recent years CMV has emerged as an important long-term determinant in the development of many chronic diseases in immunocompetent hosts.

Increased Risks

CMV is implicated in the etiology of various chronic conditions such as atherosclerosis and cardiovascular or all-cause mortality.

CMV has been identified as a risk factor for CHD A recent meta-analysis of 55 studies involving 9000 cases and

8608 controls.

Ji et al. 2012 Mol Biol Rep

Increased Risks

CMV is implicated in the etiology of various chronic conditions such as atheroslecorsis and cardiovascular or all-cause mortality.

The NHANES III study demonstrated that a positive CMV serostatus produces an increased risk for all-cause mortality, largely explained by an increase in cardiovascular deaths (CVD). High levels of CRP strengthened this association.

Simanek et al. 2011 PLoS ONE

All-cause mortality, NHANES III, n=14011 >25 years old

Increased risks

Evenmore, CMV has been implied in the development of cancer, inflammatory bowel diseases, frailty, physical and cognitive impairment in elderly.

But this association seems to disappear in VERY elderly… CMV’s main impact was seen in individuals aged 55–75 at while

CMV imposed little increased risk of mortality in the most elderly (aged 75–90) – SIMANEK et al.

BELFRAIL results: VERY elderly CMV infection was not associated with functional or cognitive

impairment. Moreover, positive CMV serology was found to be negatively associated with frailty.

These apparently contradictory results may reflect a survival effect because the current study population was considerably older than the populations of older adults in previous studies.

This would cause individuals susceptible to the long-term deleterious effects of CMV exposure to be underrepresented in the cohort because they would have died at an earlier age.

The survival analysis will give us more insight into the phenotype of the octogenarians (reverse epidemiology)

Matheï C, Vaes B, Wallemacq P, Degryse J.Associations Between Cytomegalovirus Infection and Functional Impairment and Frailty in the BELFRAIL Cohort. J Am Geriatr Soc. 2011 Nov 7. doi: 10.1111/j.1532-5415.2011.03719.x. [Epub ahead of print]

BELFRAIL Results

CMV serostatus was not associated with mortality In contrast to younger populations

anti-CMV IgG titer in the highest tertile or > 250 IU/ml was associated with mortality even after adjustment for age, gender, level of education, smoking status, BMI, co-morbidity and hCRP serum level.

These findings suggest that CMV reactivation -apparent from increased anti-CMV IgG titers- in the oldest old may be frequently present in this age-category.

Matheï et al. CMV, inflammation and mortality in the oldest old: results from the Belfrail study. Submitted

BELFRAIL – Survival Curve

Control of CMV reactivation

We hypothesize that many among the oldest old represent a phenotype that is less susceptible for the detrimental effects of CMV because of their capacity to strongly control the infection and thereby preventing reactivation and exerting harm.

However, some will eventually fail to contain the virus because of exhaustion of the immune system causing the infection to reactivate and anti-CMV IgG titers to increase.

From this perspective, high anti-CMV IgG titers in the oldest old should be interpreted as a measure of general deterioration. Rather than that it plays an important role in the etiology of mortality.

Through what mechanism exerts CMV its effect?

The mechanisms behind these associations are not fully understood

but it is believed that CMV may contribute to the chronic inflammatory state underlying most chronic diseases

as a result of periodic re-activations.

Chronic CMV hypothesis

Immunosenescence !!!

What is immunosenescence?

Immunosenescence = deleterious age-associated changes to both innate and adaptive immunity

Hallmarks: Inflammageing T-cell senescence (primarly CD8+)

Late-stage effector-memory CD8+ T-cell accumulation

In CMV-seropositive elderly, up to 50% of the overall CD8+ T-cell pool will be specific for CMV.

It remains unclear why CMV alone as such a profound impact, and not other herpesviruses. It might be due to its abundant presence in the body and efficient interaction with immune cells.

Take-home messages

CMV also appears to have long-term effects in

immunocompetent hosts (CHD, CVD, cancer, frailty,…)

Possibly trough an effect on immunosenescence

Effect disappears in the oldest old

Possibly through survivors effect

Reverse epidemiology

Thank you for your attention!

Acknowledgements:

- Jean-Marie Degryse

- Cathy Matheï

- Gijs Van Pottelbergh

- Bert Vaes

- Pierre Wallemacq