UWL: Association With Outcomes (2009)

Study Design:
- Click here for explanation of classification scheme.
Quality Rating:
Research Purpose:

To evaluate the association between asymptomatic chronic cytomegalovirus infection and the frailty syndrome and to assess whether inflammation modifies this association.

Inclusion Criteria:
  • Disabled community-dwelling women participating in the Women's Health and Aging Studies I and II
  • Aged 70 to 79
  • Baseline measures of cytomegalovirus, interleukin-6 and frailty status.
Exclusion Criteria:

Excluded if data was incomplete.

Description of Study Protocol:


Participants from the Women's Health and Aging Study, I and II, which are population-based, prospective, observational studies developed with the goal of determining the causes and natural history of physical disability. Subjects were derived from a random sample of the Health Care Financing Administration's Medicare enrollment file for 32,658 women aged 65 and older and residing in 12 contiguous zip code areas in Baltimore, Maryland.


Cross-sectional analysis of cohort study.

Statistical Analysis

  • Continuous variables were compared using student's T-test and the chi-square test was used for categorical variables
  • Multinomial logistic regression adjusted for potential confounders
  • Study-specific probability weights were used to reference inferences derived from the study subjects back to the sampling population of community-dwelling women aged 70 to 79
  • Probability weights were incorporated into all of the descriptive and regression analyses.
Data Collection Summary:

Timing of Measurements

  • Measurements were made at baseline
  • At enrollment for both studies, extensive information was collected using standardized questionnaires on demographic characteristics and history of physician diagnosis of diseases, including diabetes mellitus and congestive heart failure
  • Trained physicians used disease ascertainment algorithms to validate the presence of 17 major chronic diseases and conditions based upon the enrollment interview, physical examination, current medication list and questionnaires sent  to the subject's primary care physician. 

Dependent Variables

Cytomegalovirus serology and interleukin-6 concentrations were measured using ELISA.

Independent Variables

  • Frailty status was based on previously validated criteria: Unintentional weight loss (more than 10% since age 60), weak grip strength, exhaustion, slow walking speed and low level of activity
  • Frail women had three or more of the five components, pre-frail women had one or two components and women who were not frail had none of the components
  • Physical activity level was determined using the modified Minnesota Leisure Time Activities Questionnaire.

Control Variables

  • Age
  • Smoking history
  • Elevated BMI
  • Diabetes mellitus
  • Congestive heart failure.
Description of Actual Data Sample:
  • Initial N: 864 eligible women from both WHAS I and II. Resulting sample of 735 women with cytomegalovirus serology
  • Attrition (final N): 706 women had complete data and were included in the analysis.


Aged 70 to 79 years:

  • Cytomegalovirus-negative: Mean age, 73.5±0.3 years
  • Cytomegalovirus-positive: Mean age, 74.3±0.1 years.


  • Cytomegalovirus-negative: 92.8% Caucasian
  • Cytomegalovirus-positive: 75.5% Caucasian.


Women who participated in the blood drawing in both studies were not significantly different from women who did not participate by race or BMI but did have higher education and income, were better self-rated health and were less frail than those who did not have blood drawn.


Baltimore, Maryland. 


Summary of Results:



Cytomegalovirus-negative (N=92)

Cytomegalovirus-positive (N=632)


Frailty status, N (percentage)



5 (4.7)

87 (11.8)


Pre-frail 36 (38.1) 293 (43.6)  
Not frail 51 (57.2) 252 (44.6)  
Interleukin-6, pg per ml      
Mean ± SE 4.1±0.7  4.9±0.4  0.05 
More than 4.2 (top tertile), N (percentage) 25 (26.7) 213 (31.9) 0.34

BMI, kg/m2

Mean ± SE 25.4±0.6  27.8±0.3  <0.001 
Category, N (percentage)     <0.001 
More than 25 41 (43.6)  414 (66.1)   
More than 18.5 and less than 25 48 (54.6) 176 (29.4)  
Less than 18.5 2 (1.8) 25 (4.5)  
Walking speed, m per s, mean ± SE 1.0±0.03 0.9±0.02 <0.001
Slow, N (percentage) 16 (15.7) 231 (32.9) 0.001
Grip strength, kg, mean ± SE 23.9±0.7 23.2±0.3 0.41
Weak, N (percentage) 12 (12.6) 140 (21.1) 0.08

Other Findings

  • 87% of women were cytomegalovirus-positive, an indication of chronic infection
  • 12.7% were classified as frail, 45.4% as pre-frail and 41.9% as not frail
  • Cytomegalovirus was associated with prevalent frailty, adjusting for age, smoking history, elevated BMI, diabetes mellitus and congestive heart failure (CMV frail adjusted odds ratio = 3.2, P=0.03; CMV pre-frail AOR=1.5, P=0.18)
  • Interleukin-6 interacted with cytomegalovirus, significantly increasing the magnitude of this association (CMV positive and low IL-6 frail AOR=1.5, P=0.53; CMV positive and high IL-6 frail AOR = 20.3, P=0.007; CMV positive and low IL-6 pre-frail AOR=0.9, P=0.73; CMV positive and high IL-6 pre-frail AOR=5.5, P=0.001). 
Author Conclusion:

This cross-sectional study of community-dwelling older women suggests a novel association between cytomegalovirus and the frailty syndrome, an important outcome in older adults. Even more importantly, this study demonstrates a significant synergy between this common, chronic viral infection and the pro-inflammatory cytokine interleukin-6 that is supported by previous work and biological plausibility. Additional studies, in younger as well as older adults, may lead to greater understanding of the mechanisms underlying frailty and disability. Further prospective studies are needed to further characterize these relationships and determine whether chronic cytomegalovirus infection leads to an increased risk of developing frailty.

Funding Source:
Government: NIA, NIH, and National Center for Research Resources, Outpatient Department
Reviewer Comments:

Authors note that nutritional status, subclinical vascular disease, psychological stress and social support are examples of other factors that could influence inflammation and thus cytomegalovirus reactivation and the development of frailty; unfortunately, data about these characteristics were limited in this population.

Quality Criteria Checklist: Primary Research
Relevance Questions
  1. Would implementing the studied intervention or procedure (if found successful) result in improved outcomes for the patients/clients/population group? (Not Applicable for some epidemiological studies) N/A
  2. Did the authors study an outcome (dependent variable) or topic that the patients/clients/population group would care about? Yes
  3. Is the focus of the intervention or procedure (independent variable) or topic of study a common issue of concern to dieteticspractice? Yes
  4. Is the intervention or procedure feasible? (NA for some epidemiological studies) N/A
Validity Questions
1. Was the research question clearly stated? Yes
  1.1. Was (were) the specific intervention(s) or procedure(s) [independent variable(s)] identified? Yes
  1.2. Was (were) the outcome(s) [dependent variable(s)] clearly indicated? Yes
  1.3. Were the target population and setting specified? Yes
2. Was the selection of study subjects/patients free from bias? Yes
  2.1. Were inclusion/exclusion criteria specified (e.g., risk, point in disease progression, diagnostic or prognosis criteria), and with sufficient detail and without omitting criteria critical to the study? Yes
  2.2. Were criteria applied equally to all study groups? N/A
  2.3. Were health, demographics, and other characteristics of subjects described? Yes
  2.4. Were the subjects/patients a representative sample of the relevant population? Yes
3. Were study groups comparable? Yes
  3.1. Was the method of assigning subjects/patients to groups described and unbiased? (Method of randomization identified if RCT) Yes
  3.2. Were distribution of disease status, prognostic factors, and other factors (e.g., demographics) similar across study groups at baseline? Yes
  3.3. Were concurrent controls or comparisons used? (Concurrent preferred over historical control or comparison groups.) Yes
  3.4. If cohort study or cross-sectional study, were groups comparable on important confounding factors and/or were preexisting differences accounted for by using appropriate adjustments in statistical analysis? Yes
  3.5. If case control study, were potential confounding factors comparable for cases and controls? (If case series or trial with subjects serving as own control, this criterion is not applicable.) Yes
  3.6. If diagnostic test, was there an independent blind comparison with an appropriate reference standard (e.g., "gold standard")? N/A
4. Was method of handling withdrawals described? Yes
  4.1. Were follow-up methods described and the same for all groups? Yes
  4.2. Was the number, characteristics of withdrawals (i.e., dropouts, lost to follow up, attrition rate) and/or response rate (cross-sectional studies) described for each group? (Follow up goal for a strong study is 80%.) Yes
  4.3. Were all enrolled subjects/patients (in the original sample) accounted for? Yes
  4.4. Were reasons for withdrawals similar across groups? N/A
  4.5. If diagnostic test, was decision to perform reference test not dependent on results of test under study? N/A
5. Was blinding used to prevent introduction of bias? Yes
  5.1. In intervention study, were subjects, clinicians/practitioners, and investigators blinded to treatment group, as appropriate? Yes
  5.2. Were data collectors blinded for outcomes assessment? (If outcome is measured using an objective test, such as a lab value, this criterion is assumed to be met.) Yes
  5.3. In cohort study or cross-sectional study, were measurements of outcomes and risk factors blinded? Yes
  5.4. In case control study, was case definition explicit and case ascertainment not influenced by exposure status? N/A
  5.5. In diagnostic study, were test results blinded to patient history and other test results? N/A
6. Were intervention/therapeutic regimens/exposure factor or procedure and any comparison(s) described in detail? Were interveningfactors described? Yes
  6.1. In RCT or other intervention trial, were protocols described for all regimens studied? N/A
  6.2. In observational study, were interventions, study settings, and clinicians/provider described? Yes
  6.3. Was the intensity and duration of the intervention or exposure factor sufficient to produce a meaningful effect? N/A
  6.4. Was the amount of exposure and, if relevant, subject/patient compliance measured? N/A
  6.5. Were co-interventions (e.g., ancillary treatments, other therapies) described? N/A
  6.6. Were extra or unplanned treatments described? N/A
  6.7. Was the information for 6.4, 6.5, and 6.6 assessed the same way for all groups? N/A
  6.8. In diagnostic study, were details of test administration and replication sufficient? N/A
7. Were outcomes clearly defined and the measurements valid and reliable? Yes
  7.1. Were primary and secondary endpoints described and relevant to the question? N/A
  7.2. Were nutrition measures appropriate to question and outcomes of concern? Yes
  7.3. Was the period of follow-up long enough for important outcome(s) to occur? N/A
  7.4. Were the observations and measurements based on standard, valid, and reliable data collection instruments/tests/procedures? Yes
  7.5. Was the measurement of effect at an appropriate level of precision? Yes
  7.6. Were other factors accounted for (measured) that could affect outcomes? ???
  7.7. Were the measurements conducted consistently across groups? Yes
8. Was the statistical analysis appropriate for the study design and type of outcome indicators? Yes
  8.1. Were statistical analyses adequately described and the results reported appropriately? Yes
  8.2. Were correct statistical tests used and assumptions of test not violated? Yes
  8.3. Were statistics reported with levels of significance and/or confidence intervals? Yes
  8.4. Was "intent to treat" analysis of outcomes done (and as appropriate, was there an analysis of outcomes for those maximally exposed or a dose-response analysis)? N/A
  8.5. Were adequate adjustments made for effects of confounding factors that might have affected the outcomes (e.g., multivariate analyses)? Yes
  8.6. Was clinical significance as well as statistical significance reported? Yes
  8.7. If negative findings, was a power calculation reported to address type 2 error? N/A
9. Are conclusions supported by results with biases and limitations taken into consideration? Yes
  9.1. Is there a discussion of findings? Yes
  9.2. Are biases and study limitations identified and discussed? Yes
10. Is bias due to study's funding or sponsorship unlikely? Yes
  10.1. Were sources of funding and investigators' affiliations described? Yes
  10.2. Was the study free from apparent conflict of interest? Yes