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To the Editor: Clinically meaningful cytomegalovirus (CMV) infection is not limited to immunocompromised hosts,¹ as recently demonstrated in critically ill immunocompetent patients.² Cytomegalovirus may have an increasing effect in an aging society. Cross-sectional analyses have shown its association with frailty and functional impairment^3-4 and, along with seropositivity to other herpesviruses, an association with impaired cognition among community-dwelling older individuals.⁵ We therefore prospectively studied the association between CMV IgG levels and mortality.

Methods
These analyses are secondary analyses of the Drugs and Evidence-Based Medicine in the Elderly (DEBATE) trial. The 400 participants were recruited from 4821 randomly selected community-living individuals in Helsinki, Finland, during 1999 and 2000.⁶ The DEBATE trial was approved by the ethics committee and participants provided written consent. The mean age was 80 years (range, 75-90 years; 65% women) (Table 1), and all participants had a history of cardiovascular disease that was stable at baseline.

View this table: [in this window] [in a new window] [as a PowerPoint slide]   Table 1. Baseline Characteristics of Participants According to Cytomegalovirus IgG Level (n = 383)

Of the participants, 383 were assayed for serum IgG antibodies using an enzyme immunoassay for CMV (VIDAS CMV IgG; bioMérieux, Marcy l’Etoile, France; lowest detectable titer = 4, seropositivity defined as >4) and for Helicobacter pylori (Pyloriset EIA; Orion Diagnostica, Espoo, Finland)⁵; 17 were not tested because of technical reasons, and these participants were not clinically different. Mortality through June 30, 2007, was ascertained from registers. Baseline CMV antibody titers were divided in quartiles, and their association with mortality tested. One-way analysis of variance and ² test were used to compare continuous variables and proportions, respectively. Cox proportional hazards models were used for multivariable analyses. The proportionality assumption was met, and covariates were age, sex, and H pylori seropositivity (to control for another infection) along with variables that differed at P < .10 between CMV quartiles (Table 1) or between the 7-year survivors and nonsurvivors (diastolic blood pressure; smoking; peak expiratory flow; and levels of hemoglobin, alanine aminotransferase, C-reactive protein, high-density lipoprotein cholesterol, and creatinine). Analyses were performed with NCSS 2004 (NCSS, Kaysville, Utah). Significance was defined as 2-sided P < .05.

Results
Baseline CMV IgG antibody levels ranged from 4 to 400 U/mL, with only 35 participants (9.1%) CMV seronegative (titer = 4). (Table 1). During the 7-year follow-up, 154 participants died: 52 (33.8%), 34 (22.1%), 26 (16.9%), and 39 (25.3%) from coronary, other cardiovascular, cancer, and other causes, respectively (cause unavailable in 3 cases). Deaths occurred in 145 participants who were seropositive (41.7%) and 9 who were seronegative (25.7%) (age- and sex-adjusted hazard ratio, 1.63; 95% confidence interval [CI], 0.83-3.21). Compared with the lowest CMV quartile, mortality was significantly greater in the highest CMV quartile (Table 2); the distributions of causes of death were not significantly different (P = .86). In the fully adjusted model, hazard ratio in the highest quartile was 2.23 (95% CI, 1.32-3.79).

View this table: [in this window] [in a new window] [as a PowerPoint slide]   Table 2. Cytomegalovirus IgG Level and Total Mortality During 7-Year Follow-up

Comment
These findings support an independent association between CMV IgG antibody level and 7-year mortality in community-living older adults. The association was independent of H pylori infection and C-reactive protein level, suggesting a specific effect of CMV rather than infection or inflammation. Study limitations include all participants having a history of stable cardiovascular disease, which may limit the generalizability. Also, we measured anti-CMV antibody titers, not viral load. Although higher CMV antibody levels in aging populations may reflect subclinical reactivation,⁴ it is also possible that antibody levels become elevated by a less direct mechanism. Our results do not prove that CMV activity is the cause of the elevated risk for death or support treatment. Further studies of viral activity and of the possibility that antiviral intervention might reduce the risk will be required to test such a hypothesis. Likewise, controlled intervention studies with anti-CMV therapy would be needed to learn whether such expensive and potentially toxic therapy would be efficacious and clinically justified.

Author Contributions: Dr Strandberg had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Strandberg, Pitkala, Tilvis.

Acquisition of data: Strandberg, Pitkala.

Analysis and interpretation of data: Strandberg, Pitkala, Tilvis.

Drafting of the manuscript: Strandberg.

Critical revision of the manuscript for important intellectual content: Strandberg, Pitkala, Tilvis.

Statistical analysis: Strandberg, Tilvis.

Obtained funding: Strandberg, Pitkala.

Administrative, technical, or material support: Strandberg, Pitkala, Tilvis.

Financial Disclosures: None reported.

Funding/Support: This study was supported by grant 48613 from the Academy of Finland, the Lions Organization (Punainen Sulka-Red Feather), the Paivikki and Sakari Sohlberg Foundation, the Ragnar Ekberg Foundation, and the University Central Hospital of Helsinki.

Role of the Sponsor: The funding sources had no role in the design and conduct of the study; in the collection, analysis, and interpretation of the data; or in the preparation, review, or approval of the manuscript.

Timo E. Strandberg, MD, PhD
timo.strandberg{at}oulu.fi
Unit of General Practice
University Hospital of Oulu
Oulu, Finland

Kaisu H. Pitkala, MD, PhD
Unit of General Practice

Reijo S. Tilvis, MD, PhD
Clinic of Internal Medicine and Geriatrics
University Central Hospital of Helsinki
Helsinki, Finland

1. Rafailidis PI, Mourtzoukou EG, Varbobitis IC, Falagas ME. Severe cytomegalovirus infection in apparently immunocompetent patients: a systematic review. Virol J. 2008;5(3):47-55. FULL TEXT | PUBMED 2. Limaye AP, Kirby KA, Rubenfeld GD; et al. Cytomegalovirus reactivation in critically ill immunocompetent patients JAMA. 2008;300(4):413-422. FREE FULL TEXT 3. Schmaltz HN, Fried LP, Xue Q-L, Walston J, Leng SX, Semba RD. Chronic cytomegalovirus infection and inflammation are associated with prevalent frailty in community-dwelling older women. J Am Geriatr Soc. 2005;53(5):747-754. FULL TEXT | ISI | PUBMED 4. Aiello AE, Haan MN, Pierce CM, Simanek AM, Liang J. Persistent infection, inflammation, and functional impairment in older Latinos. J Gerontol A Biol Sci Med Sci. 2008;63(6):610-618. PUBMED 5. Strandberg TE, Pitkala K, Linnavuori KH, Tilvis RS. Impact of viral and bacterial burden on cognitive impairment in elderly persons with cardiovascular diseases. Stroke. 2003;34(9):2126-2131. FREE FULL TEXT 6. Strandberg TE, Pitkala K, Bergling S, Nieminen MS, Tilvis RS. Multifactorial cardiovascular disease prevention in patients aged 75 years and older: a randomized controlled trial. Am Heart J. 2001;142(6):945-951. FULL TEXT | ISI | PUBMED

Letters Section Editor: Robert M. Golub, MD, Senior Editor.

JAMA. 2009;301(4):380-382.

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