Association of Herpesvirus Response Burden with Long-Term Mortality Differs Between Older Males and Females

BackgroundSex-specific immune responses may contribute to variable vulnerability for Covid-19 between females and males. We tested whether there is a long-term mortality difference between sexes for other microbes (viral and bacterial) response burden among older people. MethodsSeven-year follow-up study consisted of 382 home-dwelling people aged 75-90 years (65.2% females) with a history cardiovascular disease. At baseline, serum immunoglobulin G antibodies were assayed against herpesviruses (CMV, HSV-1 and HSV-2) and bacteria (Chlamydophila pneumoniae, Mycoplasma pneumonia, and Helicobacter pylori). Titers were summed up as herpes (HB) or bacterial response burden (BB) and divided into tertiles. Hazard ratios (HR) of total mortality with 95% CIs were calculated using Cox regression. ResultsThe overall HB was lower and BB higher among males than females (P<0.001). There was a significant sex/HB (P=0.01) and sex/BB (P=0.03) interaction with mortality. Multivariable-adjusted (age, body mass index, C-reactive protein, and comorbidity index) mortality HRs for increasing HB sex-specific tertiles were 1.0 (reference), 1.34 (95% CI 0.62-2.88), and 2.66 (1.25-5.64) for males and 1.0, 1.30 (0.76-2.21), and 1.30 (0.77-2.22) for females. The significant age-adjusted association between BB and mortality in males attenuated after multivariable adjustments, HR (top-vs-bottom tertile) 1.74 (0.93-3.25). In females, no association with BB was observed. Using HB and BB as continuous variables supported the findings with tertiles. ConclusionsAlthough being lower in older males than females, higher Herpesviridae response burden was associated with increased 7-year mortality risk among males, not among females. Immune responses to common microbes may contribute to sex differences in longevity and mortality. Key points- Gender differences in vulnerability during Covid-19 has increased interested in sex-related responses to infections - We used IgG titers of Herpesviridae and bacteria as surrogate markers for variably recurrent reactivation - Although Herpesviridae response burden was generally lower among males than females, within sexes higher Herpesviridae burden strongly predicted 7-year mortality among males but not females - Long-term virus burden, like Herpesviridae, may partly explain shorter longevity and higher mortality among males with weaker immune systems