Download Longterm effects of CMV in the elderly

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
tion to an outcome that is established at the start of the
study. Most sources of error due to confounding and bias
are more common in retrospective studies than in prospective studies. To investigate whether there was the
heterogeneity of different study design, we stratified the
group by the study design, and found that there was significant heterogeneity among retrospective studies (P =
0.000), but not among prospective studies, which showed
that the heterogeneity among all the 55 studies may arise
from the difference in study design. In 6 prospective
studies, no significant heterogeneity (P = 0.054) was
observed and the ORs (1.31, 95% CI = 1.13–1.52) was
lower than the overall ORs (1.673) and the ORs (1.79) of
the 49 retrospective studies. In our meta-analysis, all 6
nested case–control studies from non-Asian populations (4
USA studies, 1 Netherlands study, 1 UK study), resulting
in the lower risks of CMV than Asian population (OR,
2.69) and retrospective studies. Thus, it is necessary to
conduct more prospective studies using standardized
unbiased methods and well matched controls among
Asian population.
and CHD risk
Among 42 included studies, detection of antibodies for
CMV IgG was performed using a commercially available
enzyme-linked immunosorbent assay (ELISA) kit, other
seven studies used a more sensitive test, PCR assay. The
various detection methods of CMV infection can bring out
the different prevalence of CMV positive radio in the
included studies. In our present study, the increased risks
(OR, 8.12) in PCR studies was significant higher than the
risks among ELISA studies (OR, 1.561,). These findings
virtually confirmed the major relationship between CMV
infection and CHD risk in various detection methods of
CMV infection.
Some limitations of this meta-analysi s should be
acknowledged. Firstly, heterogeneity is a potential problem
when interpreting all the results of meta-analyses. Although
we minimized the likelihood by performing a careful search
for published studies, using the explicit criteria for study
inclusion, performing data extraction and data analysis
strictly, the significant between-study heterogeneity still
Table 2 Main results of pooled odds ratios (OR) with confidence interval (CI) in the meta-analysis
Number of the
included studies
Heterogeneity Test (Q test)
OR (95% CI)
P (Pooled OR test)
55
Q = 258.47; P = 0.000
1.673 (1.562–1.792)
0.000
Asian
25
Q = 87.04; P = 0.000
2.691(2.304–3.144)
0.000
Non-Asian
30
Q = 139.11; P = 0.000
1.481(1.371–1.600)
0.000
Total
Ethnicity (all)
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.15325415.2011.03719.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