CMV Impairs Immunity

The professional fraudsters of the Surgeon General gang pretend that smoking supposedly impairs smokers' immune systems. But this claim is based on the deliberate scientific fraud of ignoring the role of CMV, which in infected persons is the single largest burden on the immue system! They cynically exploit the fact that smokers and passive smokers are more likely to have been exposed to this virus, for socioeconomic reasons.

CMV and Hospital Patients

Occult herpes family viruses may increase mortality in critically ill surgical patients. CH Cook, JK Yenchar, TO Kraner, EA Davies, RM Ferguson. Am J Surg 1998 Oct;176(4):357-360. "Twenty eligible patients had positive viral cultures during the study period, and 85% of these patients developed subsequent bacterial and/or fungal infections. Mortality was significantly higher following viral infection than in chronic SICU patients (65% vs 35%, P <0.006). Patients with thrombocytopenia complicating their viral infection had significantly higher mortality than those without thrombocytopenia (92% vs 25%, P <0.004). CONCLUSIONS: At least 14% of critically ill surgical patients have occult infection or reactivation of herpes family viruses. These viruses have known immunosuppressive effects, which may predispose chronic SICU patients to subsequent bacterial and fungal infection, and subsequent organ system failure and death."

Cook - Am J Surg 1998 abstract / PubMed

A novel link between stress and human cytomegalovirus (HCMV) infection: sympathetic hyperactivity stimulates HCMV activation. S Prösch, CE Wendt, P Reinke, C Priemer, M Oppert, DH Krüger, HD Volk, WD Döcke. Virology 2000 Jul 5;272(2):357-365. "Here, we demonstrate that a highly stressful event in the absence of systemic inflammation, as observed in patients with acute myocardial infarction, leads to the development of an active HCMV infection in latently infected patients. Elucidating the molecular mechanism of virus activation, we could show that catecholamines directly stimulate the HCMV immediate-early (IE) enhancer/promoter in monocytic cells via beta-2 adrenergic receptors. Subsequent activation of the cAMP/PK-A-signaling pathway results in enhanced synthesis and binding of the transcription factor CREB-1/ATF-1 to the cAMP-responsive elements within the IE enhancer. Epinephrine also enhanced HCMV gene expression in infected THP-1 cells by about 50% in three of four experiments."

Prösch - Virology 2000 abstract / PubMed

Human cytomegalovirus infections in nonimmunosuppressed critically ill patients. A Heininger, G Jahn, C Engel, T Notheisen, K Unertl, K Hamprecht. Crit Care Med 2001 Mar;29(3):541-547. 56 immunocompetent intensive care patients after major surgery or trauma. 20 (35.6%) experienced HCMV reactivation. "In patients with active HCMV infection, the mortality tended to be higher (55%) than in those without (36%); the duration of intensive care treatment of the survivors was significantly longer in the patients with active HCMV infection (median 30 vs. 23 days; p = .0375). Univariate testing for factors associated with active HCMV infection showed the importance of sepsis at admission (p = .011) and prolonged pretreatment on the ward or in an external ICU (p = .002); the relevance of underlying malignant disease was borderline (p = .059). Multiple regression analysis identified only sepsis to be independently associated with active HCMV infection (p = .02; odds ratio, 4.62)."

Heininger - Crit Care Med 2001 abstract / PubMed

Occult herpes family viral infections are endemic in critically ill surgical patients. CH Cook, LC Martin, JK Yenchar, MC Lahm, B McGuinness, EA Davies, RM Ferguson. Crit Care Med 2003 Jul;31(7):1923-1929. "Weekly cultures for cytomegalovirus (CMV) and herpes simplex virus, viral serologies, and T-cell counts were performed. The prevalence (95% confidence interval) of positive respiratory cultures for herpes simplex or CMV was 35% (22-49%); 15% (5-25%) cultured positive for CMV, 23% (11-35%) cultured positive for herpes simplex virus, and one patient's respiratory secretions culturing positive for both CMV and herpes simplex virus. The prevalence of CMV viremia was only 5.8% (1-10%). CMV+ patients had longer hospital admissions, intensive care unit admissions, and periods of ventilator dependence than CMV- patients, despite having comparable severity of illness scores. CMV+ patients also had significantly higher numbers of blood transfusions, prevalence of steroid exposure, and prevalence of hepatic dysfunction, and all were immunoglobulin G positive at the beginning of the study."

Cook - Crit Care Med 2003 abstract / PubMed

Cytomegalovirus infection in critically ill patients: associated factors and consequences. S Jaber, G Chanques, J Borry, B Souche, R Verdier, PF Perrigault, JJ Eledjam. Chest 2005 Jan;127(1):233-241. 237 patients with fever for > 72 h, none HIV+ or transplant. CMV reactivated within 20 days in 20%. "CMV infection was linked to renal failure (58% vs 33%, respectively; p = 0.02) and steroid use (55% vs 33%, respectively; p = 0.04). Patients with CMV had a significantly longer stay in the ICU (41 +/- 28 days vs 31 +/- 22 days, respectively; p = 0.04), a longer duration of mechanical ventilation (35 +/- 27 days vs 24 +/- 20 days, respectively; p = 0.03), a higher rate of nosocomial infection (75% vs 50%, respectively; p = 0.04), and a higher mortality (50% vs 28%, p = 0.02)."

Jaber / Chest 2005 full article

Active cytomegalovirus infection in patients with septic shock. L von Müller, A Klemm, M Weiss, M Schneider, H Suger-Wiedeck, N Durmus, W Hampl, T Mertens. Emerg Infect Dis 2006 Oct;12(10):1517-1522. Prospective study of 25 immunocompetent CMV-seropositive patients with septic shock and an intensive care unit stay of > or =7 days. "Within 2 weeks, active CMV infection with low-level pp65-antigenemia (median 3 positive/5x10(5) leukocytes) developed in 8 (32%) patients. Infection was controlled within a few weeks (median 26 days) without use of antiviral therapy. Duration of intensive care and mechanical ventilation were significantly prolonged in patients with active CMV infection. CMV reactivation was associated with concomitant herpes simplex virus reactivation (p = 0.004)."

von Müller / Emerg Infect Dis 2006 full article (pdf, 159 pp, on p. 45)
von Müller - Emerg Infect Dis 2006 full article / PubMed Central

Cytomegalovirus Reactivation in "Immunocompetent" Patients: A Call for Scientific Prophylaxis. CH Cook. J Infect Dis 2007;196(9):1273-1275. "During critical illness—and specifically sepsis—CMV is reactivated in ~30% of these latently infected individuals, a finding that has now been reproduced independently by 4 different groups.. Because these reactivation episodes are "controlled" by the immune system, one might argue that they are of no clinical consequence. Indeed, as best as can be told, patients with reactivation do not appear to be dying of fulminant CMV disease. Nonetheless, clinical studies published to date have demonstrated surprisingly consistent morbidity in these patients. Nonimmunosuppressed critically ill patients with CMV reactivation require increased duration of mechanical ventilation, prolonged hospitalization, and may have worsened survival."

Cook / J Infect Dis 2007 full article

Cytomegalovirus reactivation in critically ill immunocompetent patients. AP Limaye, KA Kirby, GD Rubenfeld, WM Leisenring, EM Bulger, MJ Neff, NS Gibran, ML Huang, TK Santo Hayes, L Corey, M Boeckh. JAMA 2008 Jul 23;300(4):413-422. 120 CMV-seropositive, immunocompetent adults. "Cytomegalovirus viremia at any level occurred in 33% (39/120; 95% confidence interval [CI], 24%-41%) at a median of 12 days (range, 3-57 days) and CMV viremia greater than 1000 copies/mL occurred in 20% (24/120; 95% CI, 13%-28%) at a median of 26 days (range, 9-56 days). By logistic regression, CMV infection at any level (adjusted odds ratio [OR], 4.3; 95% CI, 1.6-11.9; P = .005) and at greater than 1000 copies/mL (adjusted OR, 13.9; 95% CI, 3.2-60; P < .001) and the average CMV area under the curve (AUC) in log(10) copies per milliliter (adjusted OR, 2.1; 95% CI, 1.3-3.2; P < .001) were independently associated with hospitalization or death by 30 days. In multivariable partial proportional odds models, both CMV 7-day moving average (OR, 5.1; 95% CI, 2.9-9.1; P < .001) and CMV AUC (OR, 3.2; 95% CI, 2.1-4.7; P < .001) were independently associated with a hospital length of stay of at least 14 days."

Limaye / JAMA 2008 full article
Limaye - JAMA 2008 full article / PubMed Central

Cytomegalovirus reactivation and associated outcome of critically ill patients with severe sepsis. A Heininger, H Haeberle, I Fischer, R Beck, R Riessen, F Rohde, C Meisner, G Jahn, A Koenigsrainer, K Unertl, K Hamprecht. Crit Care 2011 Mar1;15(2):R77. Adult nonimmunosuppressed CMV-seropositive patients with new onset of severe sepsis. "CMV reactivation occurred in 35 of the 86 (40.69%) analysed patients... In patients with and without CMV reactivation mortality rates were similar (37.1% vs. 35.3%, P = 0.861), respectively. However, in the multivariate COX regression analyses CMV reactivation was independently associated with increased length of stay in the ICU."

Heininger - Crit Care 2011 full article / PubMed Central
Heininger / Crit Care 2011 full article

The role of viruses in nosocomial pneumonia. L Chiche, JM Forel, L Papazian. Curr Opin Infect Dis 2011 Apr;24(2):152-6. Review. Concerning immunocompetent hospital patients: "Patients infected with these viruses [HSV and CMV] show increased morbidity and, especially for CMV, mortality. An increase of bacterial or fungal superinfections was observed in ICU patients with CMV reactivation."

Chiche - Curr Opin Infect Dis 2011 abstract / PubMed

Cytomegalovirus infection in severe burn patients monitoring by real-time polymerase chain reaction: A prospective study. J Bordes, J Maslin, B Prunet, E d'Aranda, G Lacroix, P Goutorbe, E Dantzer, E Meaudre. Burns 2011 May;37(3):434-439. 29 immunocompetent burn patients with total burn surface area greater than 15%. "CMV reactivation was associated with a higher IGS 2 score on admission. High grade CMV viremia was associated with longer mechanical ventilation duration, higher infection number, higher transfused red blood cell number, and longer ICU stays. There were no differences on mortality rate between patients with and without CMV reactivation."

Bordes - Burns 2011 abstract / PubMed

Immune risk phenotype is associated with nosocomial lung infections in elderly in-patients. A Plonquet, S Bastuji-Garin, F Tahmasebi, C Brisacier, K Ledudal, J Farcet, E Paillaud. Immun Ageing 2011 Oct 1;8:8. 97 nosocomial infections among 252 consecutive in-patients aged 70 years or over. "The main infection sites were the respiratory tract (21%) and urinary tract (17.1%) When we compared immunological parameters including cell counts determined by flow cytometry in the groups with and without nosocomial infections, we found that the group with nosocomial infections had significantly lower values for the CD4/CD8 ratio and naive CD8 and CD4 T-cell counts and higher counts of memory CD8 T-cells with a significant increase in CD28-negative CD8-T cells. Neither cytomegalovirus status (positive in 193/246 patients) nor presence of the IRP was associated with nosocomial infections. However, nosocomial pneumonia was significantly more common among IRP-positive patients than IRP-negative patients (17/60 versus 28/180; p = 0.036)."

Plonquet - Immun Ageing 2011 full article / PubMed Central
Plonquet / Immun Ageing 2011 full article

Molecular detection of microorganisms in distal airways of patients undergoing lung cancer surgery. XB D'Journo, F Bittar, D Trousse, F Gaillat, C Doddoli, H Dutau, L Papazian, D Raoult, JM Rolain, PA Thomas. Ann Thorac Surg 2012 Feb;93(2):413-422. 87 patients. All were negative for the bacterial 16s ribosomal RNA gene by PCR. "Thirteen patients (15%) had a positive CMV PCR (positive-PCR group), whereas the remaining 74 patients constituted the negative-PCR group. Postoperative pneumonia occurred in 24% of the negative-PCR group and in 69% of the positive-PCR group (p = 0.003). Upon stepwise logistic regression, performance status, percent of predicted diffusion lung capacity for carbon monoxide, and positive PCR were the risk factors of postoperative respiratory complications. The CMV PCR had a positive predictive value of 0.70 in prediction of respiratory complications."

D'Journo - Ann Thorac Surg 2012 abstract / PubMed
D'Journo / Ann Thorac Surg 2012 full article

Viral infections in septic shock (VISS-trial)-crosslinks between inflammation and immunosuppression. T Brenner, C Rosenhagen, I Hornig, K Schmidt, C Lichtenstern, M Mieth, T Bruckner, E Martin, P Schnitzler, S Hofer, MA Weigand. J Surg Res 2012 Aug;176(2):571-582. 60 patients with septic shock. "Thirty-one patients (51.7%) were found to be positive for HSV-1, whereas in 16 patients (26.7%) CMV could be identified. Patients with a positive PCR for HSV-1 and/or CMV showed a significantly prolonged length of hospital stay and absolute time of respirator-dependant ventilation. Furthermore, survival curves of patients with a high HSV-1-load (>10E8) in tracheal secretion in comparison with those with a lower HSV-1-load (<10E8) revealed a significantly impaired survival."

Brenner - J Surg Res 2012 abstract / PubMed

Interferon-γ production by natural killer cells and cytomegalovirus in critically ill patients. L Chiche, JM Forel, G Thomas, C Farnarier, C Cognet, C Guervilly, C Zandotti, F Vély, A Roch, E Vivier, L Papazian. Crit Care Med 2012 Dec;40(12):3162-3169. "Fifty-one subjects, including 15 patients who experienced cytomegalovirus reactivation (cases) during their intensive care unit stay and 15 patients who matched intensive care unit controls, selected from a cohort of consecutive nonimmunocompromised intensive care unit patients, as well as healthy controls... No differences of natural killer cell effector functions were observed at admission between cases and controls. Instead, before cytomegalovirus reactivation, the ability of natural killer cells to secrete interferon-γ was significantly reduced in cases as compared with controls upon stimulation with antibody-coated target cells (p = .029) and with K562 cell stimulation (p = .029). No phenotypic or quantitative differences were observed between cases and controls. Cases exhibited higher levels of interleukin 10 (p = .031) and interleukin 15 (p = .021) than controls before cytomegalovirus reactivation."

Chiche - Crit Care Med 2012 abstract / PubMed

Cytomegalovirus and herpes simplex virus effect on the prognosis of mechanically ventilated patients suspected to have ventilator-associated pneumonia. Y Coisel, S Bousbia, JM Forel, S Hraiech, B Lascola, A Roch, C Zandotti, M Million, S Jaber, D Raoult, L Papazian. PLoS One 2012;7(12):e51340. 93 patients with suspected pneumonia. "We identified 22 patients with a CMV infection, 26 patients with an HSV infection and 45 patients without CMV or HSV infection (control group). Mortality at day 60 was higher in patients with a CMV infection than in patients from the control group (55% vs. 20%, P<0.01). Mortality at day 60 was not significantly increased in the group with HSV infection. Duration of ICU stay and ICU mortality were significantly higher in patients with CMV infections when compared to patients from the control group, whereas ventilator free days were significantly lower in patients with CMV infections when compared to patients from the control group."

Coisel - PLoS One 2012 full article / PubMed Central
Coisel - PLoS One 2012 full article

Reactivation of multiple viruses in patients with sepsis. AH Walton, JT Muenzer, D Rasche, JS Boomer, B Sato, BH Brownstein, A Pachot, TL Brooks, E Deych, WD Shannon, JM Green, GA Storch, RS Hotchkiss. PLoS One 2014 Jun 11;9(2):e98819. 560 critically-ill septic, 161 critically-ill non-septic, and 164 healthy age-matched patients. "Patients with protracted sepsis had markedly increased frequency of detectable virus. Cumulative viral DNA detection rates in blood were: CMV (24.2%), EBV (53.2%), HSV (14.1%), HHV-6 (10.4%), and TTV (77.5%). 42.7% of septic patients had presence of two or more viruses. The 50% detection rate for herpesviruses was 5-8 days after sepsis onset. A small subgroup of septic patients had markedly elevated viral loads (>104-106 DNA copies/ml blood) for CMV, EBV, and HSV. Excluding TTV, DNAemia was uncommon in critically-ill non-septic patients and in age-matched healthy controls. Compared to septic patients without DNAemia, septic patients with viremia had increased fungal and opportunistic bacterial infections. Patients with detectable CMV in plasma had higher 90-day mortality compared to CMV-negative patients; p<0.05. Reactivation of latent viruses is common with prolonged sepsis, with frequencies similar to those occurring in transplant patients on immunosuppressive therapy and consistent with development of an immunosuppressive state."

Walton - PLoS One 2014 full article / PubMed Central
Walton / PLoS One 2014 full article

Cytomegalovirus reactivation in a general, nonimmunosuppressed intensive care unit population: Incidence, risk factors, associations with organ dysfunction, and inflammatory biomarkers. FG Frantzeskaki, ES Karampi, C Kottaridi, M Alepaki, C Routsi, M Tzanela, DA Vassiliadi, E Douka, S Tsaousi, V Gennimata, I Ilias, N Nikitas, A Armaganidis, P Karakitsos, V Papaevangelou, I Dimopoulou. J Crit Care 2015 Apr;30(2):276-281. 80 patients. "Reactivation of CMV occurred in 11 patients (13.75%). Median day of reactivation was day 7 post ICU admission. Total number of red blood cell units transfused (odds ratio [OR], 1.50; confidence interval [CI], 1.06-2.13; P = .02) and C-reactive protein levels upon ICU admission (OR, 1.01; CI, 1.00-1.02; P = .02) were independently associated with CMV reactivation. High IL-10 was marginally related to reactivation (P = .06). Sequential Organ Failure Assessment scores were higher in the group with CMV reactivation compared with patients without reactivation during the entire 28-day observation period (P < .006). Salivary cortisol, mortality, length of ICU stay, and duration of mechanical ventilation were similar in the 2 groups."

Frantzeskaki - J Crit Care 2015 abstract / PubMed

Coreactivation of Human Herpesvirus 6 and Cytomegalovirus Is Associated With Worse Clinical Outcome in Critically Ill Adults. PL Roa, JA Hill, KA Kirby, WM Leisenring, ML Huang, TK Santo, KR Jerome, M Boeckh, AP Limaye. Crit Care Med 2015 Jul;43(7):1415-1422. 115 CMV+ immunocompetent adults. "Human herpesvirus 6 viremia occurred in 23% of patients at a median of 10 days. Human herpesvirus 6B was the species detected in eight samples available for testing. Most patients with human herpesvirus 6 reactivation also reactivated cytomegalovirus (70%). Severity of illness was not associated with viral reactivation. Mechanical ventilation, burn ICU, major infection, human herpesvirus 6 reactivation, and cytomegalovirus reactivation were associated with the primary endpoint in unadjusted analyses. In a multivariable model adjusting for mechanical ventilation and ICU type, only coreactivation of human herpesvirus 6 and cytomegalovirus was significantly associated with the primary endpoint (adjusted odds ratio, 7.5; 95% CI, 1.9-29.9; p = 0.005) compared to patients with only human herpesvirus 6, only cytomegalovirus, or no viral reactivation."

Roa - Crit Care Med 2015 abstract / PubMed

Cytomegalovirus reactivation and mortality in patients with acute respiratory distress syndrome. DS Ong, C Spitoni, PM Klein Klouwenberg, FM Verduyn Lunel, JF Frencken, MJ Schultz, T van der Poll, J Kesecioglu, MJ Bonten, OL Cremer. Intensive Care Med 2016 Mar;42(3):333-341. "Of 399 ARDS patients, 271 (68 %) were CMV seropositive and reactivation occurred in 74 (27 %) of them. After adjustment for confounding and competing risks, CMV reactivation was associated with overall increased ICU mortality (adjusted subdistribution hazard ratio (SHR) 2.74, 95 % CI 1.51-4.97), which resulted from the joint action of trends toward an increased mortality rate (direct effect; cause specific hazard ratio (HR) 1.58, 95 % CI 0.86-2.90) and a reduced successful weaning rate (indirect effect; cause specific HR 0.83, 95 % CI 0.58-1.18). These associations remained in sensitivity analyses. The population-attributable fraction of ICU mortality was 23 % (95 % CI 6-41) by day 30 (risk difference 4.4, 95 % CI 1.1-7.9)."

Ong - Intensive Care Med 2016 abstract / PubMed

Cytomegalovirus infection in patients with sepsis due to bloodstream infections: lower risk and better outcomes in new versus already hospitalised intensive care unit admissions. R Osawa, M Wagener, NS Singh. Anaesth Intensive Care 2016 Sep;44(5):571-80. "CMV viraemia developed in 20% (20/100) of the patients... There was no difference in the primary endpoint (mortality and/or multi-organ failure) between patients with and without CMV viraemia (P=0.49). However, CMV viraemia was associated with significantly fewer ICU-free days (P=0.023) and fewer ventilator-free days (P=0.031)."

Osawa - Anaesth Intensive Care 2016 abstract / PubMed

Systemic inflammation after critical illness: relationship with physical recovery and exploration of potential mechanisms. DM Griffith, S Lewis, AG Rossi, J Rennie, L Salisbury, JL Merriweather, K Templeton, TS Walsh; RECOVER Investigators. Thorax 2016 Sep;71(9):820-829. 123 surviving adult ICU patients. "Patients seropositive for HCMV at ICU discharge (63%) had a more proinflammatory phenotype at 3 months than seronegative patients, despite undetectable HMCV by PCR testing."

Griffith - Thorax 2016 abstract / PubMed

Association Between Cytomegalovirus Reactivation and Clinical Outcomes in Immunocompetent Critically Ill Patients: A Systematic Review and Meta-Analysis. P Lachance, J Chen, R Featherstone, WI Sligl. Open Forum Infect Dis 2017 Feb 13;4(2):ofx029. 22 studies. "CMV reactivation was associated with increased ICU mortality (odds ratio [OR], 2.55; 95% confidence interval [CI], 1.87-3.47), overall mortality (OR, 2.02; 95% CI, 1.60-2.56), duration of mechanical ventilation (mean difference 6.60 days; 95% CI, 3.09-10.12), nosocomial infections (OR, 3.20; 95% CI, 2.05-4.98), need for RRT (OR, 2.37; 95% CI, 1.31-4.31), and ICU length of stay (mean difference 8.18 days; 95% CI, 6.14-10.22)."

Lachance - Open Forum Infect Dis 2017 full article / PubMed Central
Lachance / Open Forum Infect Dis 2017 full article

Effect of Ganciclovir on IL-6 Levels Among Cytomegalovirus-Seropositive Adults With Critical Illness: A Randomized Clinical Trial. AP Limaye, RD Stapleton, L Peng, SR Gunn, LE Kimball, R Hyzy, MC Exline, DC Files, PE Morris, SK Frankel, ME Mikkelsen, D Hite, KB Enfield, J Steingrub, J O'Brien, PE Parsons, J Cuschieri, RG Wunderink, DL Hotchkin, YQ Chen, GD Rubenfeld, M Boeckh. JAMA 2017 Aug 22;318(8):731-740. 160 randomized patients. "The ganciclovir group had more median VFDs [ventilator-free days] in both the intention-to-treat (ITT) group and in the prespecified sepsis subgroup (ITT group: 23 days in ganciclovir group vs 20 days in the placebo group, P = .05; sepsis subgroup, 23 days in the ganciclovir group vs 20 days in the placebo group, P = .03)." Mortality was 12% vs 15%, nonsignificant.

Limaye - JAMA 2017 abstract / PubMed

Cytomegalovirus Serostatus as Predictor for Adverse Events After Cardiac Surgery: A Prospective Observational Study. M Ziemann, M Heringlake, P Lenor, D Juhl, T Hanke, M Petersen, J Schön, H Heinze, HV Groesdonk, H Paarmann, H Hennig. J Cardiothorac Vasc Anesth 2017 Dec;31(6):2042-2048. 983 patients. "618 patients were found to be seropositive for CMV (63%). Among these, the risk for reintubation was increased (10% v 4%, p = 0.001). This increase remained significant after correction for confounding factors (odds ratio 2.70, p = 0.003) and was detectable from the third postoperative day throughout the whole postoperative period."

Ziemann - J Cardiothorac Vasc Anesth 2017 abstract / PubMed

A National Survey of the Prevalence and Impact of Cytomegalovirus Infection Among Hospitalized Patients With Ulcerative Colitis. LB Grossberg, G Ezaz, D Grunwald, J Cohen, KR Falchuk, JD Feuerstein. J Clin Gastroenterol 2018 Mar;52(3):241-245. "Patients with UC and CMV (n=145) had longer length of stay (16.31 vs. 5.52 d, P<0.0001), higher total charges ($111,835.50 vs. $39.895, P=0.001), and were less likely to be discharged home without services (50.0% vs. 81.83%, P<0.0001) compared with patients with UC without CMV (n=32,290). On regression analysis, CMV was significantly associated with higher total charges (P<0.01) and longer length of stay (P<0.01), but not for increased need for colorectal surgery."

Grossberg - J Clin Gastroenterol 2018 abstract / PubMed

Cytomegalovirus infection and outcome in immunocompetent patients in the intensive care unit: a systematic review and meta-analysis. X Li, Y Huang, Z Xu, R Zhang, X Liu, Y Li, P Mao. BMC Infect Dis 2018 Jun 28;18(1):289. 2398 immunocompetent patients admitted to ICUs. "The odds ratio (OR) for all-cause mortality among patients with CMV infection, compared with those without infection, was 2.16 (95%CI 1.70-2.74, I2 = 10%, n = 2239). Moreover, upon exclusion of studies in which antiviral treatment was possibly or definitely provided to some patients, the association of mortality rate with CMV infection was also statistically significant (OR: 1.69, 95%CI 1.01-2.83, I2 = 37%, n = 912,). For CMV seropositive patients, the OR for mortality in patients with CMV reactivation as compared with patients without CMV reactivation was 1.72 (95%CI 1.04-2.85, I2 = 29%, n = 664). Patients with CMV infection required significantly longer mechanical ventilation (mean difference (MD): 9 days (95% CI 5-14, I2 = 81%, n = 875)) and longer duration of ICU stay (MD: 12 days (95% CI 7-17, I2 = 70%, n = 949)) than patients without CMV infection."

Li - BMC Infect Dis 2018 full article / PubMed Central
Li / BMC Infect Dis 2018 full article

Reactivation of Latent Cytomegalovirus Infection after Major Surgery: Risk Factors and Outcomes. BJ Gardiner, KW Herrick, RC Bailey, JK Chow, DR Snydman. Surg Infect (Larchmt) 2019 Jul;20(5):416-423. 16 cases, 32 controls. "Despite similar baseline comorbidities, cases were more likely to return to surgery (odds ratio [OR] 6.31; 95% confidence interval [CI], 1.29-30.74), require renal replacement therapy (OR 18.54; 95% CI, 2.36-145.6), total parenteral nutrition (OR 33.0; 95% CI, 6.60-262.37) and corticosteroids (OR 18.78; 95% CI, 4.5-103.9). Length of stay was increased (median 51 vs. 8 days, p = 0.005), co-infections were more common (OR 15.10; 95% CI, 1.89-120.8), and mortality was higher (38% vs. 0%, p < 0.01)."

Gardiner - Surg Infect (Larchmt) 2019 abstract / PubMed

[Analysis of clinical characteristics and risk factors of cytomegalovirus reactivation in immunocompetent patients in respiratory intensive care unit]. X Wang, YN Liu, Z Jin, JJ Huang, JF Huang, JP Liao, J Ma, GF Wang. Zhonghua Yi Xue Za Zhi 2019 Oct 29;99(40):3168-3171. 11 patients reactivated, 70 non-."Length of RICU stay were longer in the group with CMV reactivation compared to patients without CMV reactivation [54(50, 68) vs 32(17, 43) d, P=0.012]."

Wang - Zhonghua Yi Xue Za Zhi 2019 abstract / PubMed

Herpes simplex virus and Cytomegalovirus reactivation among severe ARDS patients under veno-venous ECMO. S Hraiech, E Bonnardel, C Guervilly, C Fabre, A Loundou, JM Forel, M Adda, G Parzy, G Cavaille, B Coiffard, A Roch, L Papazian. Ann Intensive Care 2019 Dec 23;9(1):142. 123 non-immunocompromised patients. "When considered separately, both HSV and CMV reactivation were associated with a longer duration of MV as compared to non-reactivation patients [29 (19.5-41) and 28 (20.5-37), respectively, vs. 17.5 (9-28) days; p < 0.05]. Co-reactivation patients had a longer duration of MV [58.5 (38-72.3); p < 0.05] and ICU stay [51.5 (32.5-69) vs. 27.5 (17.75-35.5) and 29 (20-30.5), respectively] as compared to patients with HSV or CMV reactivation alone."

Hraiech - Ann Intensive Care 2019 full article / PubMed Central

Cytomegalovirus Reactivation in Patients With Sepsis in an Intensive Care Unit in Portugal. P Paixão, P Ramos, C Piedade, A Casado, M Chasqueira. Acta Med Port 2020 Sep 1;33(9):576-582. 8 of 22 ICU patients had CMV reactivation. "No association was found between cytomegalovirus reactivation and gender, age, length of Intensive Care unit stay, duration of mechanical ventilation, and patient death... However, patients with cytomegalovirus reactivation had a longer hospital stay from Intensive Care unit entry to hospital discharge or patient death (p = 0.025)."

Paixão - Acta Med Port 2020 abstract / PubMed

CMV and Aging

Age-related change in peripheral blood T-lymphocyte subpopulations and cytomegalovirus infection in the very old: the Swedish longitudinal OCTO immune study. J Olsson, A Wikby, B Johansson, S Löfgren, BO Nilsson, FG Ferguson. Mech Ageing Dev 2000 Dec 20;121(1-3):187-201. "In the present study immune system changes were identified that suggest a loss of T-cell homeostasis, as reflected by a decrease in the number of CD4 cells and a very significant increase in the number of CD8 cells in individuals with an inverted CD4/CD8 ratio. When considered over the duration of the OCTO study the inversion occurred in a high percentage (32%) of the individuals included in the original sample and was associated with non-survival. At T4 the changes were apparent in a number of the T-cell subsets, but particularly in the CD8+CD28-and CD57+ subsets. T-cell activation was significantly associated with the inversion of the CD4/CD8 ratio. In this very old sample the subset alterations were associated with evidence of cytomegalovirus (CMV) infection."

Olsson - Mech Ageing Dev 2000 abstract / PubMed

Expansions of peripheral blood CD8 T-lymphocyte subpopulations and an association with cytomegalovirus seropositivity in the elderly: the Swedish NONA immune study. A Wikby, B Johansson, J Olsson, S Lofgren, BO Nilsson, F Ferguson. Exp Gerontol 2002 Jan 3;37(2-3):445-453. "Results from a previous longitudinal study, the Swedish OCTO-Immune study, indicated that the combination of higher CD8 peripheral blood lymphocytes (PBLs), decreased CD4 PBLs, and poor proliferative response to mitogenic stimulation in very old humans were associated with an increased 2 year mortality... As in the OCTO study, the NONA-Immune data indicated that the changes are associated significantly with seropositive responses to CMV."

Wikby - Exp Gerontol 2002 abstract / PubMed

Expansion of peripheral CD8+ T cells in patients with coronary artery disease: relation to cytomegalovirus infection. L Jonasson, A Tompa, A Wikby. J Intern Med 2003 Nov;254(5):472-478. 43 patients with angina and angiographically verified CAD, versus 69 clinically healthy controls. "An expansion of CD8+ T cells expressing CD57 but lacking CD28 was seen in the patient group. The numbers of CD8+ CD57+ and CD8+ CD28-T-cell subsets were independently related to CMV seropositivity (P<0.001) but also to CAD per se (P<0.05). Serum concentrations of C-reactive protein (CRP) and soluble interleukin-2 receptor (sIL-2R) were elevated in the patients but not related to CMV or CD8+ T-cell subsets."

Jonasson - J Intern Med 2003 abstract / PubMed

Emergence of a CD4+CD28- granzyme B+, cytomegalovirus-specific T cell subset after recovery of primary cytomegalovirus infection. EM van Leeuwen, EB Remmerswaal, MT Vossen, AT Rowshani, PM Wertheim-van Dillen, RA van Lier, IJ ten Berge. J Immunol 2004 Aug 1;173(3):1834-1841. "In this study, we show that in primary CMV infections, CD4(+)CD28(-) T cells emerge just after cessation of the viral load, indicating that infection with CMV triggers the formation of CD4(+)CD28(-) T cells. In line with this, we found these cells only in CMV-infected persons. CD4(+)CD28(-) cells had an Ag-primed phenotype and expressed the cytolytic molecules granzyme B and perforin. Importantly, CD4(+)CD28(-) cells were to a large extent CMV-specific because proliferation was only induced by CMV-Ag, but not by recall Ags such as purified protein derivative or tetanus toxoid. CD4(+)CD28(-) cells only produced IFN-gamma after stimulation with CMV-Ag, whereas CD4(+)CD28(+) cells also produced IFN-gamma in response to varicella-zoster virus and purified protein derivative. Thus, CD4(+)CD28(-) T cells emerge as a consequence of CMV infection."

van Leeuwen / J Immunol 2004 full article

Different contribution of EBV and CMV infections in very long-term carriers to age-related alterations of CD8+ T cells. R Vescovini, A Telera, FF Fagnoni, C Biasini, MC Medici, P Valcavi, P di Pede, G Lucchini, L Zanlari, G Passeri, F Zanni, C Chezzi, C Franceschi, P Sansoni. Exp Gerontol 2004 Aug;39(8):1233-1243. In nonagenarians and centenarians, "The frequency and absolute number of CD8+ T cells specific for one lytic and two latent EBV-epitopes, were relatively low and mostly included within CD8+ CD28+ cells. By contrast, CMV infection was characterized by highly variable numbers of CD8+ T cells specific for two differently restricted CMV-epitopes that, in some subjects, were strikingly expanded. Moreover, the great majority of anti-CMV CD8+ T cells did not bear CD28 antigen. Notwithstanding the expansion of CMV-specific CD8+ lymphocytes, CMV-DNA detection in blood samples was invariably negative. Altogether, we suggest that CMV, but not EBV, can sustain chronic activation of the HLA-class I restricted effector arm in elderly that might have detrimental effects on age-associated diseases."

Vescovini - Exp Gerontol 2004 abstract / PubMed

Herpesvirus-specific CD8 T cell immunity in old age: cytomegalovirus impairs the response to a coresident EBV infection. N Khan, A Hislop, N Gudgeon, M Cobbold, R Khanna, L Nayak, AB Rickinson, PA Moss. J Immunol 2004 Dec 15;173(12):7481-7489. "CMV appears to be the most immunogenic, with the CD8 T cell response representing over 10% of the CD8 pool in many elderly donors. Interestingly, the effect of age upon EBV-specific responses depends upon donor CMV sero-status. In CMV seropositive donors, the magnitude of the EBV-specific immune response is stable with age, but in CMV seronegative donors, the response to EBV increases significantly with age. By contrast, the influenza-specific CD8 T cell immune response decreases with age, independent of CMV status."

Khan / J Immunol 2004 full article

Broadly targeted human cytomegalovirus-specific CD4+ and CD8+ T cells dominate the memory compartments of exposed subjects. AW Sylwester, BL Mitchell, JB Edgar, C Taormina, C Pelte, F Ruchti, PR Sleath, KH Grabstein, NA Hosken, F Kern, J. A Nelson, and LJ Picker. J Exp Med 2005;202(5):673-685. "We further documented that total HCMV-specific T cell responses in seropositive subjects were enormous, comprising on average ~10% of both the CD4+ and CD8+ memory compartments in blood, whereas cross-reactive recognition of HCMV proteins in seronegative individuals was limited to CD8+ T cells and was rare." "Although there are few comparative data for pan-proteome immunogenicity analysis of other human viral infections, previous reports assessing T cell responses to viral lysates, infected cells, or immunodominant epitopes strongly suggest that the frequencies of HCMV-specific T cells in healthy subjects considerably exceed those observed for other common viruses, including measles, mumps, influenza, adenovirus, poxvirus, and even other persistent Herpes family viruses (e.g., Herpes simplex, Herpes zoster) and are comparable with frequencies of HIV-specific T cells in active HIV infection." "[O]ur observation that ~30% of adult subjects have HCMV-specific populations comprising >20% of their circulating CD4+ and/or CD8+ memory T cell repertoire suggests that HCMV-specific T cell responsiveness might be excessive in some individuals, perhaps with detrimental clinical effects." "...T cell recognition of HCMV is complex, often very broad, and poorly approximated by responses to any one or two HCMV ORFs."

Sylwester / J Exp Med 2005 full article

Long-term cytomegalovirus infection leads to significant changes in the composition of the CD8+ T-cell repertoire, which may be the basis for an imbalance in the cytokine production profile in elderly persons. G Almanzar, S Schwaiger, B Jenewein, M Keller, D Herndler-Brandstetter, R Wurzner, D Schonitzer, B Grubeck-Loebenstein. J Virol 2005 Mar;79(6):3675-3683. "CD8+ T cells were analyzed in young, middle-aged, and elderly clinically healthy persons with a positive or negative CMV antibody serology. Numbers and functional properties of CMVpp65(495-503)-specific CD8+ T cells were also studied. We demonstrate that aging as well as CMV infection lead to a decrease in the size of the naive CD8+ T-cell pool but to an increase in the number of CD8+ effector T cells, which produce gamma interferon but lack substantial growth potential. The size of the CD8+ memory T-cell population, which grows well and produces interleukin-2 (IL-2) and IL-4, also increases with aging, but this increase is missing in CMV carriers. Life-long latent CMV infection seems thus to diminish the size of the naive and the early memory T-cell pool and to drive a Th1 polarization within the immune system. This can lead to a reduced diversity of CD8 responses and to chronic inflammatory processes which may be the basis of severe health problems in elderly persons."

Almanzar - J Virol 2005 full article / PubMed Central
Almanzar / J Virol 2005 full article

Chronic cytomegalovirus infection and inflammation are associated with prevalent frailty in community-dwelling older women. HN Schmaltz, LP Fried, QL Xue, J Walston, SX Leng, RD Semba. J Am Geriatr Soc 2005 May;53(5):747-754. 724 women. "Frailty status was based on previously validated criteria: unintentional weight loss, weak grip strength, exhaustion, slow walking speed, and low level of activity... Eighty-seven percent of women were CMV seropositive, an indication of chronic infection. CMV was associated with prevalent frailty, adjusting for age, smoking history, elevated body mass index, diabetes mellitus, and congestive heart failure (CMV frail adjusted odds ratio (AOR)=3.2, P=.03; CMV prefrail AOR=1.5, P=.18). IL-6 interacted with CMV, significantly increasing the magnitude of this association (CMV positive and low IL-6 frail AOR=1.5, P=.53; CMV positive and high IL-6 frail AOR=20.3, P=.007; CMV positive and low IL-6 prefrail AOR=0.9, P=.73; CMV positive and high IL-6 prefrail AOR=5.5, P=.001)."

Schmaltz - J Am Geriatr Soc 2005 abstract / PubMed

Cytomegalovirus-specific CD4+ T cells in healthy carriers are continuously driven to replicative exhaustion. JM Fletcher, M Vukmanovic-Stejic, PJ Dunne, KE Birch, JE Cook, SE Jackson, M Salmon, MH Rustin, AN Akbar. J Immunol 2005 Dec 15;175(12):8218-8225. "We found that CMV-specific CD4+ T cells were significantly expanded in healthy young and old carriers compared with purified protein derivative-, varicella zoster virus-, EBV-, and HSV-specific populations. These CMV-specific CD4+ T cells exhibited a late differentiated phenotype since they were largely CD27 and CD28 negative and had shorter telomeres. Interestingly, in elderly CMV-seropositive subjects, CD4+ T cells of different specificities were significantly more differentiated than the same cells in CMV-seronegative individuals. This suggested the involvement of bystander-secreted, differentiation-inducing factors during CMV infection. One candidate was IFN-alpha, which induced loss of costimulatory receptors and inhibited telomerase in activated CD4+ T cells and was secreted at high levels by CMV-stimulated plasmacytoid dendritic cells (PDC). The CMV-specific CD4+ T cells in elderly subjects had severely restricted replicative capacity. This is the first description of a human memory T cell population that is susceptible to being lost through end-stage differentiation due to the combined effects of lifelong virus reactivation in the presence of bystander differentiation-inducing factors."

Fletcher / J Immunol 2005 full article

Interleukin 12 induces T-cell recruitment into the atherosclerotic plaque. X Zhang, A Niessner, T Nakajima, W Ma-Krupa, SL Kopecky, RL Frye, JJ Goronzy, CM Weyand. Circ Res 2006 Mar 3;98(4):524-531. "(CD4+)CD28- T cells, either isolated from the plaque tissue or from the blood of patients with acute coronary syndrome (ACS), spontaneously express interleukin (IL)-12 receptors, even in the absence of antigenic stimulation." In human atheroma-SCID mouse chimeras, "Exposure of nonstimulated (CD4+)CD28- T cells to IL-12 was sufficient to amplify T-cell accumulation within the inflamed plaque, and coadministration of anti-CCR5 antibodies blocked T-cell recruitment into the plaque. Thus, (CD4+)CD28- T cells functionally resemble NK cells, which have proinflammatory activity even in the unprimed state and respond to any IL-12-inducing host infection with a shift in tissue trafficking and accrual in inflammatory lesions."

Zhang / Circ Res 2006 full article

The immune risk phenotype is associated with IL-6 in the terminal decline stage: findings from the Swedish NONA immune longitudinal study of very late life functioning. A Wikby, BO Nilsson, R Forsey, J Thompson, J Strindhall, S Lofgren, J Ernerudh, G Pawelec, F Ferguson, B Johansson. Mech Ageing Dev 2006 Aug;127(8):695-704. "IRP and low-grade inflammation predicted 57% of observed deaths and 97% of survival over 2 years, and was not significantly affected by individuals' health status, suggesting that the physiological ageing processes of T-cell immunosenescence and low-grade inflammation are of primary importance in late life survival. IRP non-survivors showed only a minor inflammatory activity at baseline, but had in contrast to survivors developed increased activity at follow-up. The results suggest a sequence of stages for IRP individuals that begin with acquisition of CMV infection in earlier life, followed by generation of CD8+CD28- cells to control persistent CMV infection and eventually the development of an IRP. Intriguingly, we also found that rare individuals moved out of the IRP category by a process of immune suppression, including increases in IL-6 and IL-10 and decreases in the number of CD3+CD8+CD28- cells."

Wikby - Mech Ageing Dev 2006 abstract / PubMed

Strong selection of virus-specific cytotoxic CD4+ T-cell clones during primary human cytomegalovirus infection. EM van Leeuwen, EB Remmerswaal, MH Heemskerk, IJ ten Berge, RA van Lier. Blood 2006 Nov 1;108(9):3121-3127. "In the acute response, CMV-specific CD4+ T cells are highly activated and proliferating, have a CD45RA+CD45R0+CD28+CD27+ phenotype, and produce IFN after stimulation with CMV antigen in vitro. Late after primary infection, CMV-specific CD4+ T cells have returned to a resting stage, and the percentage of IFN-producing CMV-specific CD4+ T cells is considerably lower than during the acute infection. Moreover, a considerable number of CMV-specific CD4+ T cells have progressed toward a further differentiated phenotype, characterized by the loss of both CD27 and CD28 and the acquisition of cytolytic molecules such as perforin and granzyme B (grB). CD4+CD28– grB+ T cells appear to be characteristic for CMV infection because they emerge after primary CMV infection and can be found only in CMV-seropositive individuals. Consequently, proliferation and cytokine production by CD4+CD28– T cells can be induced by CMV but not by other viral antigens."

van Leeuwen / Blood 2006 full article

Massive Load of Functional Effector CD4+ and CD8+ T Cells against Cytomegalovirus in Very Old Subjects. R Vescovini, C Biasini, FF Fagnoni, AR Telera, L Zanlari, M Pedrazzoni, L Bucci, D Monti, MC Medici, C Chezzi, C Franceschi, and P Sansoni. J Immunol 2007;179: 4283-4291. "Results indicate that pp65 and, to a lesser extent, IE-1 constitute major Ags against which aged people target functionally efficient T cell effector responses with massive production of Th1 cytokines and exhibition of CD107a degranulation marker. As a result, the production of IFN- induced in T cells by both Ags was seven to eight times greater in very old than in young subjects. The comparative analysis of pp65-specific responses in these very long-term carriers revealed a reciprocal relationship between CD4+ and CD8+ producing IFN- in the same individuals. These results indicate that CMV represents an important pathogen responsible for a strong immune activation in human aging. Such a remarkable burden of effector CD4+ and CD8+ T cells may be necessary to protect the elderly from CMV endogenous reactivation, but can turn detrimental by giving a substantial contribution to the proinflammatory status that accompanies the main age-related diseases."

Vescovini / J Immunol 2007 abstract

Unchecked CD70 expression on T cells lowers threshold for T cell activation in rheumatoid arthritis. WW Lee, ZZ Yang, G Li, CM Weyand, JJ Goronzy. J Immunol 2007 Aug 15;179(4):2609-2615. Expression of CD70 was the most striking difference between CD4(+)CD28(-) and CD4(+)CD28(+) T cells; and "CD70 on bystander CD4(+)CD28(-) T cells functioned by lowering the threshold for T cell activation; admixture of CD4(+)CD28(-) T cells augmented TCR-induced responses of autologous naive CD4(+)CD28(+) T cells, particularly of low-avidity T cells."

Lee - J Immunol 2007 abstract / PubMed

Cytomegalovirus Infection: A Driving Force in Human T Cell Immunosenescence. S Koch, A Larbi, D Ozcelik, R Solana, C Gouttefangeas, S Attig, A Wikby, J Strindhall, C Franceschi, G Pawelec. Ann N Y Acad Sci 2007 Oct;1114:23-35. REVIEW. "It has recently emerged that the common herpesvirus, cytomegalovirus (CMV), which establishes persistent, life-long infection, usually asymptomatically, may well be the driving force behind clonal expansions and altered phenotypes and functions of CD8 cells seen in most old people. In those few who are not CMV-infected, another even more common herpesvirus, the Epstein-Barr virus, appears to have the same effect. These virus-driven changes are less marked in "successfully aged" centenarians, but most marked in people whom longitudinal studies have shown to be at higher risk of death, that is, those possessing an "immune risk profile" (IRP) characterized by an inverted CD4:8 ratio (caused by the accumulation primarily of CD8(+) CD28(-) cells). These findings support the hypothesis that persistent herpesviruses, especially CMV, act as chronic antigenic stressors and play a major causative role in immunosenescence and associated mortality."

Koch - Ann N Y Acad Sci 2007 abstract / PubMed

Functional killer Ig-like receptors on human memory CD4+ T cells specific for cytomegalovirus. J van Bergen, EM Kooy-Winkelaar, H van Dongen, FA van Gaalen, A Thompson, TW Huizinga, MC Feltkamp, RE Toes, F Koning. J Immunol 2009 Apr 1;182(7):4175-4182. "Although very few CD4(+) T cells express killer Ig receptors (KIR), a large proportion of CD4(+) T cells with a late memory phenotype, characterized by the absence of CD28, does express KIR. Here, we show that KIR expression on CD4(+) T cells is also associated with memory T cell function, by showing that the frequency of CMV-specific cells is higher in CD4(+)KIR(+) than CD4(+)KIR(-) T cells. In addition, engagement of an inhibitory KIR inhibited the CMV-specific proliferation of these CD4(+)KIR(+) memory T cells, but had no detectable effect on cytokine production. Our data reveal that, in marked contrast with CD8(+) T cells, the activity of a subset of CMV-specific CD4(+) T cells is modulated by HLA class I-specific KIR. Thus, the CMV-induced down-regulation of HLA class I may in fact enhance memory CMV-specific CD4(+) T cell responses restricted by HLA class II."

van Bergen - J Immunol 2009 abstract / PubMed

Cytomegalovirus infection reduces telomere length of the circulating T cell pool. PJ van de Berg, SJ Griffiths, SL Yong, R Macaulay, FJ Bemelman, S Jackson, SM Henson, IJ en Berge, AN Akbar, RA van Lier. J Immunol 2010 Apr 1;184(7):3417-3423. "After primary CMV infection, we observed an increase in highly differentiated cells that coincided with a steep drop in telomere length. Moreover, we found in a cohort of 159 healthy individuals that telomere shortening was more rapid in CMV-seropositive individuals and correlated with the amount of differentiated T cells in both CD4(+) T cells and CD8(+) T cells. Finally, we found that telomere length measured in blood leukocytes is correlated with lymphocyte telomere length."

van de Berg - J Immunol 2010 abstract / PubMed

Cytomegalovirus infection- and age-dependent changes in human CD8+ T-cell cytokine expression patterns. B Faist, B Fleischer, M Jacobsen. Clin Vaccine Immunol 2010 Jun;17(6):986-992. 59 CMV serum IgG-positive healthy donors and 20 CMV serum IgG-negative donors. "The CMV pp65 peptide pool and the superantigen Staphylococcus enterotoxin B (SEB) induced higher proportions of CD8+ effector T cells expressing gamma interferon (IFN-gamma), tumor necrosis factor alpha (TNF-alpha), and granulocyte-macrophage colony-stimulating factor in the oldest study group, while only SEB induced increased responses in the middle-aged study group. Notably, CMV-specific multiple cytokine expression patterns revealed higher proportions of IFN-gamma- and TNF-alpha-coexpressing CD8+ T cells exclusively in the oldest study group."

Faist - Clin Vaccine Immunol 2010 full article / PubMed Central
Faist - Clin Vaccine Immunol 2010 full article

Hallmark Features of Immunosenescence Are Absent in Familial Longevity. E Derhovanessian, AB Maier, R Beck, G Jahn, K Hähnel, PE Slagboom, AJ de Craen, RG Westendorp, G Pawelec. J Immunol 2010 Oct 15;185(8):4618-4624. 97 Leiden Longevity Study offspring and spouse controls. "CMV infection was strongly associated with an age-related reduction in the frequency of naive T cells and an accumulation of CD45RA-re-expressing and late-differentiated effector memory T cells in the general population, but not in members of long-lived families. The latter also had significantly lower C-reactive protein levels, indicating a lower proinflammatory status compared with CMV-infected controls. Finally, T cells from a higher proportion of offspring mounted a proliferative response against CMV Ags, which was also of greater magnitude and broader specificity than controls."

Derhovanessian / J Immunol 2010 full article

Cytomegalovirus infection induces the accumulation of short-lived, multifunctional CD4+ CD45RA+ CD27⁻ T cells: the potential involvement of interleukin-7 in this process. V Libri, RI Azevedo, SE Jackson, D Di Mitri, R Lachmann, S Fuhrmann, M Vukmanovic-Stejic, K Yong, L Battistini, F Kern, MV Soares, AN Akbar. Immunology 2011 Mar;132(3):326-339. "Using multiple linear regression analysis we found that age itself is a stronger predictor than CMV seropositivity for the decrease in CD45RA+ CD27+ CD4+ T cells over time. In contrast, the increase in CD45RA⁻ CD27⁻ and CD45RA+ CD27⁻ CD4+ T cells is almost exclusively the result of CMV seropositivity, with age alone having no significant effect. Furthermore, the majority of the CD45RA⁻ CD27⁻ and CD45RA+ CD27⁻ CD4+ T cells in CMV-seropositive donors are specific for this virus. CD45RA+ CD27⁻ CD4+ T cells have significantly reduced CD28, interleukin-7 receptor α (IL-7Rα) and Bcl-2 expression, Akt (ser473) phosphorylation and reduced ability to survive after T-cell receptor activation compared with the other T-cell subsets in the same donors... Finally we showed that the proportion of CD45RA+ CD27⁻ CD4+ T cells of multiple specificities was significantly higher in the bone marrow than the blood of the same individuals, suggesting that this may be a site where these cells are generated."

Libri - Immunology 2011 abstract / PubMed

Association of detectable cytomegalovirus (CMV) DNA in monocytes rather than positive CMV IgG serology with elevated neopterin levels in community-dwelling older adults. SX Leng, H Li, QL Xue, J Tian, X Yang, L Ferrucci, N Fedarko, LP Fried, RD Semba. Exp Gerontol 2011 Aug;46(8):679-684. "52 (73.2%) participants were CMV seropositive, of whom 30 (57.5%) had detectable CMV DNA. CMV seropositive and seronegative participants did not differ in their neopterin levels, but individuals with detectable CMV DNA had higher neopterin than those without (10.6 ± 4.4 vs 8.0 ± 1.9 nM, respectively, p<.0001) adjusting for demographic and clinical covariates and interferon (IFN)-γ levels." "As positive IgG serology does not distinguish between past and persistent infections, these results suggest that CMV seropositive older adult population is heterogeneous in regard to the status of chronic CMV infection."

Leng / Exp Gerontol 2011 full article

Expression of the RAE-1 Family of Stimulatory NK-Cell Ligands Requires Activation of the PI3K Pathway during Viral Infection and Transformation. M Tokuyama, C Lorin, F Delebecque, H Jung, DH Raulet, L Coscoy. PLoS Pathog 2011;7(9):e1002265. "We observed that MCMV activates the PI3K pathway and that this activation is required for NKG2D ligand expression. We also found that the expression of NKG2D ligands on cancer cell lines is dependent on this pathway. Our data suggest that NKG2D ligand expression, and thus recognition of infected and cancer cells by NK cells, is associated with a dysregulation in the PI3K pathway."

Tokuyama / PLoS Pathog 2011 full article

Relationship between cytomegalovirus (CMV) IgG serology, detectable CMV DNA in peripheral monocytes, and CMV pp65(495-503)-specific CD8 (+) T cells in older adults. SX Leng, T Qu, RD Semba, H Li, X Yao, T Nilles, X Yang, B Manwani, JD Walston, L Ferrucci, LP Fried, JB Margolick, JH Bream. Age (Dordr) 2011 Dec;33(4):607-614. 16 HLA-A2-positive elderly volunteers. "While all participants had positive CMV IgG serology by enzyme-linked immunosorbent assays, only nine (56%) had detectable CMV DNA by nested polymerase chain reaction. These nine individuals had significantly higher percentages of CMV pp65(495-503) tetramer-positive CD8(+) T cells (median = 1.3%) than those without detectable CMV DNA (median = 0.1%; p < 0.001). Absolute CMV IgG antibody titers did not differ between these two groups (median = 54.6 vs 44.2 EU/ml, respectively, p = 0.4)."

Leng - Age (Dordr) 2011 abstract / PubMed

Infection with cytomegalovirus but not herpes simplex virus induces the accumulation of late-differentiated CD4+ and CD8+ T-cells in humans. E Derhovanessian, AB Maier, K Hähnel, R Beck, AJ de Craen, EP Slagboom, RG Westendorp, G Pawelec. J Gen Virol 2011 Dec;92(Pt 12):2746-2756. "Individuals harbouring CMV were confirmed to possess lower frequencies of naïve CD8+ T-cells (defined as CD45RA+CCR7+CD27+CD28+) and greater proportions of late-differentiated effector memory (CD45RA-CCR7-CD27-CD28-) and so-called TEMRA (CD45RA+CCR7-CD27-CD28-) CD4 and CD8 subsets, independent of HSV seropositivity. In CMV-seronegative donors, HSV did not affect T-cell subset distribution significantly."

Derhovanessian - J Gen Virol 2011 abstract - PubMed

The Human Cytomegalovirus UL11 Protein Interacts with the Receptor Tyrosine Phosphatase CD45, Resulting in Functional Paralysis of T Cells. I Gabaev, L Steinbrück, C Pokoyski, A Pich, RJ Stanton, R Schwinzer, TF Schulz, R Jacobs, M Messerle, PC Kay-Fedorov. PLoS Pathog 2011;7(12): e1002432. "CD45 has a pivotal function regulating T cell signaling thresholds; in its absence, the Src family kinase Lck is inactive and signaling through the T cell receptor (TCR) is therefore shut off... Binding of the CMV pUL11 protein to CD45 on T cells prevents signal transduction via the TCR and restricts T cell proliferation."

Gabaev / PLoS Pathog 2011 full article

NKG2D expression in CD4+ T lymphocytes as a marker of senescence in the aged immune system. R Alonso-Arias, MA Moro-García, A López-Vázquez, L Rodrigo, J Baltar, FM García, JJ Jaurrieta, C López-Larrea. Age (Dordr) 2011 Dec;33(4):591-605. 100 healthy elders, 50 healthy young adults. "The median percentage of CD4+ T cells expressing NKG2D was almost fourfold higher in elderly volunteers (5.3% [IR: 8.74%]) than in young subjects (1.4% [IR: 1.7%])... Approximately 83% of the elderly individuals displayed CD4+ NKG2D+ T cell levels higher than 2.3%, the 75th percentile in control donors... Despite the decline of the absolute numbers of CD4+ T cells with age, elderly individuals also showed higher CD4+ NKG2D+ count than young subjects, with 30.7 (IR: 56.7) and 19.4 (IR: 18.4) cells per μL, respectively."

Alonso-Arias - Age (Dordr) 2011 full article / PubMed Central

NK-cells have an impaired response to acute exercise and a lower expression of the inhibitory receptors KLRG1 and CD158a in humans with latent cytomegalovirus infection. AB Bigley, TW Lowder, G Spielmann, JL Rector, H Pircher, JA Woods, RJ Simpson. Brain Behav Immun 2012 Jan;26(1):177-186. Twenty healthy males (age: 28.4±5.4 years). "CMVpos had lower proportions of NK-cells expressing inhibitory receptors (KLRG1+ and CD158a+) and higher proportions of terminally differentiated NK-cells (KLRG1-/CD57+) compared to CMVneg. CMVpos mobilized far fewer (132 cells/μL vs. 245 cells/μL) NK-cells in response to exercise despite having similar baseline NK-cell counts and physiological responses to exercise as CMVneg, although terminally differentiated NK-cells were equally responsive to exercise regardless of CMV serostatus (p=0.658). EBVpos had higher proportions of CD8+ NK-cells, but cellular responses to exercise were not influenced by EBV. The frequency and exercise-responsiveness of γδ T-cells was not affected by CMV or EBV serostatus (p>0.05)."

Bigley - Brain Behav Immun 2012 abstract / PubMed

Early-life environment influencing susceptibility to cytomegalovirus infection: evidence from the Leiden Longevity Study and the Longitudinal Study of Aging Danish Twins. LH Mortensen, AB Maier, PE Slagbom, G Pawelec, E Derhovanessian, I Petersen, G Jahn, RG Westendorp, K Christensen. Epidemiol Infect 2012 May;140(5):835-841. 844 sib pairs plus 1452 offspring and their partners. "Offspring of the long-lived LLS participants had significantly lower seroprevalence of CMV compared to their partners (offspring: 42% vs. partners: 51%, P=0·003). Of 372 offspring living with a CMV-positive partner, only 58% were infected. The corresponding number for partners was 71% (P<0·001). In the LSADT, MZ and DZ twins had high and similar CMV-positive concordance rates (MZ: 90% vs. DZ: 88%, P=0·51) suggesting that shared family environment accounts for the similarity within twin pairs."

Mortensen - Epidemiol Infect 2012 abstract / PubMed

Deep Sequencing of Antiviral T-Cell Responses to HCMV and EBV in Humans Reveals a Stable Repertoire That Is Maintained for Many Years. PL Klarenbeek, EB Remmerswaal, IJ Ten Berge, ME Doorenspleet, BD van Schaik, RE Esveldt, SD Koch, A Ten Brinke, AH van Kampen, FJ Bemelman, PP Tak, F Baas, N de Vries, RA van Lier. PLoS Pathog 2012 Sep;8(9):e1002889. "For both viruses we found that nearly all virus-specific CD8+ T-cell clones that appeared during the early phase of infection were maintained at high frequencies during the 5-year follow-up and hardly any new anti-viral clones appeared. Both in transplant recipients and in healthy carriers the clones specific for these latent viruses were highly dominant within the CD8+ T-cell receptor Vβ repertoire." In a healthy donor, "6 of the 30 most abundant clones were directed against hCMV, mainly towards the IE epitope. These included the 5th and 8th most abundant clones. Many hCMV-pp65-specific clones were observed lower in the hierarchy. EBV specific clones made up 4 of the top 30 clones. Generally they were slightly lower in the hierarchy, the highest being ranked 9th. These findings show that also in healthy individuals many of the highly abundant clones are directed against epitopes of hCMV and EBV confirming our findings in the transplant recipients. Very large expansions of individual clones within the total CD8 T-cell repertoire detected by conventional sequencing have been reported previously."

Klarenbeek / PLoS Pathog 2012 full articleKlarenbeek - PLoS Pathog 2012 full article / PubMed Central

The Polyfunctionality of Human Memory CD8+ T Cells Elicited by Acute and Chronic Virus Infections Is Not Influenced by Age. A Lelic, CP Verschoor, M Ventresca, R Parsons, C Evelegh, D Bowdish, MR BettsMR BettsMR Betts, MB. Loeb, JL Bramson. PLoS Pathog 2012 Dec 13;8(12):e1003076. "In the aged cohort, the CD8+ T cell compartment displayed a marked reduction in the frequency of naïve CD8+ T cells and increased frequencies of CD8+ T cells that expressed CD57 and lacked CD28, as previously described. However, we did not observe an influence of age on either the frequency of virus-specific CD8+ T cells within the circulating pool nor their functionality (based on the production of IFNγ, TNFα, IL2, Granzyme B, Perforin and mobilization of CD107a). We did note that CD8+ T cells specific for WNV, CMV or EBV displayed distinct functional profiles, but these differences were unrelated to age. Collectively, these data fail to support the hypothesis that immunosenescence leads to defective CD8+ T cell immunity and suggest that it should be possible to develop CD8+ T cell vaccines to protect aged individuals from infections with novel emerging viruses." "WNV-specific CD8+ T cells produced the least IL-2, EBV-specific CD8+ T cells produced the highest amounts of IL-2 and CMV-specific CD8+ T cells displayed an intermediate phenotype."

Lelic / PLoS Pathog 2012 full article

Intensity of the humoral response to cytomegalovirus is associated with the phenotypic and functional status of the immune system. R Alonso Arias, MA Moro-García, A Echeverría, JJ Solano-Jaurrieta, FM Suárez-García, C López-Larrea. J Virol 2013 Apr;87(8):4486-4495. "[C]omparing young and elderly individuals with similar antibody levels reveals differences in their highly differentiated and naïve T cells. These are more marked in individuals with high titers. In parallel with the increase in anti-CMV antibodies, the elderly experience a significant reduction in absolute counts of naïve CD4(+) T cells, which may be a strategy to compensate for the expansion of differentiated cells and to avoid an increase in total T cells."

Alonso Arias - J Virol 2013 abstract / PubMed

Age-associated alterations in γδ T-cells are present predominantly in individuals infected with Cytomegalovirus. K Wistuba-Hamprecht, D Frasca, B Blomberg, G Pawelec, E Derhovanessian. Immun Ageing 2013 Jul 3;10(1):26. 33 healthy individuals aged between 21 and 89 years. "[W]e observed a significant age-associated accumulation of late-differentiated T-cells within the Vδ2- population, but only in CMV-seropositive donors. There was also a strong trend towards reduced frequency of early-differentiated cells within the Vδ2- phenotype. Older people had significantly higher anti-CMV IgG titers, which in turn correlated significantly with a lower Vδ2+/Vδ2- ratio and a shift from early- to a late-differentiated Vδ2- T-cell phenotype."

Wistuba-Hamprecht - Immun Ageing 2013 full article / PubMed Central
Wistuba-Hamprecht / Immun Ageing 2013 full article

Lower proportion of naïve peripheral CD8+ T cells and an unopposed pro-inflammatory response to human Cytomegalovirus proteins in vitro are associated with longer survival in very elderly people. E Derhovanessian, AB Maier, K Hähnel, H Zelba, AJ de Craen, H Roelofs, EP Slagboom, RG Westendorp, G Pawelec. Age (Dordr) 2013 Aug;35(4):1387-1399. "Counter-intuitively, we found that a lower frequency of naïve CD8+ T cells (characterized as CD45RA+CCR7+CD27+CD28+) at baseline (>88 years) correlated with significantly better survival, while there was a tendency for the reciprocal accumulation of late-differentiated effector memory cells (CD45RA-CCR7-CD27-CD28-) also to associate with better survival... We found that individuals mounting an exclusively pro-inflammatory ex vivo response (TNF, IFN-γ, IL-17) to the major CMV target molecules pp65 and IE1 had a significant survival advantage over those also having anti-inflammatory responses (IL-10)."

Derhovanessian - Age (Dordr) 2013 full article / PubMed Central

Human cytomegalovirus particles directly suppress CD4 T-lymphocyte activation and proliferation. O Fornara, J Odeberg, Z Khan, G Stragliotto, I Peredo, L Butler, C Söderberg-Nauclér. Immunobiology 2013 Aug;218(8):1034-1040. "[W]e found that HCMV directly inhibited proliferation of CD4 T cells and rendered them unresponsive to immunological stimuli. This effect was not observed when CD4 T cells were treated with herpes simplex virus-1/2 or measles virus. When stimulated with phytohemagglutinin, concanavalin A, or phorbol myristate acetate, HCMV-treated T cells were unable to proliferate, revealing an ability of HCMV to inhibit CD4 T cell response. Furthermore, HCMV also prevented proliferation of leukemic T-cell lines. HCMV-treated CD4 T cells expressed the activation markers CD45RO and CD69, were not apoptotic and produced decreased levels of the cytokines IL-4, IFN-γ and TNF-α, compared to untreated controls. The inhibitory effect of HCMV on CD4 T cell proliferation was not mediated by HCMV gH, gB or other immunogenic glycoproteins, since intravenous immunoglobulins or gB- or gH-specific neutralizing antibodies did not prevent the suppression of T-cell proliferation."

Fornara / Immunobiology 2013 abstract

Differential Impact of Age and Cytomegalovirus Infection on the γδ T Cell Compartment. A Roux, G Mourin, M Larsen, S Fastenackels, A Urrutia, G Gorochov, B Autran, C Donner, D Sidi, J Sibony-Prat, A Marchant, M Stern, D Sauce, V Appay. J Immunol 2013 Aug 1;191(3):1300-1306. "Of note, CMV infection, which is directly associated with the activation of the pool of Vδ2(-) γδ T cells, promotes nonetheless the inflation of this compartment throughout life. CMV seropositivity accentuates further the accumulation of highly differentiated lymphocytes in Vδ2(-) γδ T cell subsets with time, in contrast to Vδ2(+) γδ T cells, which maintain a less differentiated phenotype. This is similar to the effect of CMV on αβ T cells and suggests that γδ T cells may vary in differentiation phenotype according to distinct stimuli or pathogens."

Roux - J Immunol 2013 abstract / PubMed

Telomere length dynamics in human memory T cells specific for viruses causing acute or latent infections. JM O'Bryan, M Woda, M Co, A Mathew, AL Rothman. Immun Ageing 2013 Aug 26;10(1):37. 10 healthy subjects, plus 5 long term. "Frequencies of CD4+ T cells that proliferated to CMV were generally lower than the other three viruses, but were very high in two subjects... Counter to our expectation, we found that the CMV-specific CD4+ T cell TL was also significantly longer than IAV [influenza A]-specific CD4+ T cell TL (p<0.05) in both absolute TL and as a ratio to naïve T cell TL... The CMV-specific (BrdU+) CD4+ T cells with longer TLs may predominantly reflect memory T cells more recently converted from the naive repertoire. This interpretation supports the idea that CMV-specific T cell immunity is maintained by ongoing (periodic or continual) recruitment and activation of CMV-reactive naive T cells."

O'Bryan / Immun Ageing 2013 full article

Leukocyte telomere length associates with prospective mortality independent of immune-related parameters and known genetic markers. J Deelen, M Beekman, V Codd, S Trompet, L Broer, S Hägg, K Fischer, PE Thijssen, HE Suchiman, I Postmus, AG Uitterlinden, A Hofman, AJ de Craen, A Metspalu, NL Pedersen, CM van Duijn, J Wouter Jukema, JJ Houwing-Duistermaat, NJ Samani, P Eline Slagboom. Int J Epidemiol 2014;43(3):878-886. 870 nonagenarian siblings (mean age 93 years), 1580 of their offspring and 725 spouses. "We found that shorter LTL is associated with increased prospective mortality in middle (30-80 years; hazard ratio (HR) = 0.75, P = 0.001) and highly advanced age (≥90 years; HR = 0.92, P = 0.028), and show that this association cannot be explained by the association of LTL with the immune-related markers insulin-like growth factor 1 to insulin-like growth factor binding protein 3 molar ratio, C-reactive protein, interleukin 6, cytomegalovirus serostatus or white blood cell counts. We found no difference in LTL between the middle-aged LLS offspring and their spouses (β = 0.006, P = 0.932). Neither did we observe an association of LTL-associated genetic variants with mortality in a prospective meta-analysis of multiple cohorts (n = 8165)." [Note that "positive IgG serology does not distinguish between past and persistent infections," Leng 2011 - cast]

Deelen / Int J Epidemiol 2014 full article

Effects of Aging, Cytomegalovirus Infection, and EBV Infection on Human B Cell Repertoires. C Wang, Y Liu, LT Xu, KJ Jackson, KM Roskin, TD Pham, J Laserson, EL Marshall, K Seo, JY Lee, D Furman, D Koller, CL Dekker, MM Davis, AZ Fire, SD Boyd. J Immunol 2014 Jan 15;192(2):603-611. 27 subjects aged 20 to 89. "Some features of the B cell repertoire remain stable with age, but elderly subjects show increased numbers of B cells with long CDR3 regions, a trend toward accumulation of more highly mutated IgM and IgG Ig genes, and persistent clonal B cell populations in the blood. Seropositivity for CMV or EBV infection alters B cell repertoires, regardless of the individual's age: EBV infection correlates with the presence of persistent clonal B cell expansions, whereas CMV infection correlates with the proportion of highly mutated antibody genes."

Wang - J Immunol 2014 full article / PubMed Central
Wang / J Immunol 2014 full article

Rudimentary signs of immunosenescence in Cytomegalovirus-seropositive healthy young adults. JE Turner, JP Campbell, KM Edwards, LJ Howarth, G Pawelec, S Aldred, P Moss, MT Drayson, VE Burns, JA Bosch. Age (Dordr) 2014 Feb;36(1):287-297. 158 subjects, age 21 ± 3 years, 48 (30%) were CMV+. "A higher lymphocyte and CD8+ count (both p < 0.01) and a lower CD4/CD8 ratio (p < 0.03) were observed in CMV+ people. Eight percent (4/58) of CMV+ individuals exhibited a CD4/CD8 ratio <1.0, whereas no CMV- donor showed an inverted ratio (p < 0.001). The numbers of CD4+ and CD8+CD27-CD28-/CD45RA+ cells were ~ fourfold higher in CMV+ people (p < 0.001). Plasma IL-6 was higher in CMV+ donors (p < 0.05) and showed a positive association with the numbers of CD8+CD28- cells (p < 0.03). Finally, there was a significant negative correlation between vaccine-induced antibody responses to the A/Brisbane influenza strain and CMV-specific immunoglobulin G titres (p < 0.05)."

Turner - Age (Dordr) 2014 abstract / PubMed

Cytomegalovirus infection impairs immunosuppressive and antimicrobial effector functions of human multipotent mesenchymal stromal cells. R Meisel, K Heseler, J Nau, SK Schmidt, M Leineweber, S Pudelko, J Wenning, A Zimmermann, H Hengel, C Sinzger, Ö Degistirici, RV Sorg, W Däubener. Mediators Inflamm 2014;2014:898630. "We demonstrate that CMV-infected MSC lose their cytokine-induced immunosuppressive capacity and are no longer able to restrict microbial growth. IDO expression is substantially impaired following CMV infection of MSC and this interaction critically depends on intact virus and the number of MSC as well as the viral load."

Meisel - Mediators Inflamm 2014 full article / PubMed Central
Meisel / Mediators Inflamm 2014 full article

Immune biomarkers predictive of respiratory viral infection in elderly nursing home residents. J Johnstone, R Parsons, F Botelho, J Millar, S McNeil, T Fulop, J McElhaney, MK Andrew, SD Walter, PJ Devereaux, M Malekesmaeili, RR Brinkman, J Mahony, J Bramson, M Loeb. PLoS One 2014 Oct 2;9(9):e108481. 1072 residents. "269 swabs were obtained, 87 were positive for virus: influenza (24%), RSV (14%), coronavirus (32%), rhinovirus (17%), human metapneumovirus (9%) and parainfluenza (5%). In multivariable analysis, high T-reg% (HR 0.41, 95% CI 0.20-0.81) and high CMV-reactive CD4+ T-cell% (HR 1.69, 95% CI 1.03-2.78) were predictive of respiratory viral infection."

Johnstone - PLoS One 2014 full article / PubMed Central
Johnstone / PLoS One 2014 full article

Variation in the human immune system is largely driven by non-heritable influences. P Brodin, V Jojic, T Gao, S Bhattacharya, CJ Angel, D Furman, S Shen-Orr, CL Dekker, GE Swan, AJ Butte, HT Maecker, MM Davis. Cell 2015 Jan 15;160(1-2):37-47. 210 healthy twins. "We measured 204 different parameters, including cell population frequencies, cytokine responses, and serum proteins, and found that 77% of these are dominated (>50% of variance) and 58% almost completely determined (>80% of variance) by non-heritable influences. In addition, some of these parameters become more variable with age, suggesting the cumulative influence of environmental exposure. Similarly, the serological responses to seasonal influenza vaccination are also determined largely by non-heritable factors, likely due to repeated exposure to different strains. Lastly, in MZ twins discordant for cytomegalovirus infection, more than half of all parameters are affected."

Brodin - Cell 2015 abstract / PubMed

(Re Brodin 2015): Environment, not genes, plays starring role in human immune variation, study finds. Stanford Medicine News Center, Jan. 15, 2015. "In a striking example of the immune system’s plasticity, the Stanford scientists found that exposure to a single chronic, viral infection could have a massive effect on the system’s composition and responsiveness. Three out of five Americans and as many as nine out of 10 people in the developing world are chronic carriers of cytomegalovirus, which is dangerous in immune-compromised people but otherwise generally benign. In 16 of the 27 monozygotic twin pairs participating in the study, one member of the pair had been exposed to cytomegalovirus but the other had not. For nearly 60 percent of all the features Davis’ group measured, cytomegalovirus’ presence in one twin and absence in another made a big difference."

Environment, not genes, plays starring role / Stanford University

CD4:8 Ratio >5 Is Associated With a Dominant Naive T-Cell Phenotype and Impaired Physical Functioning in CMV-Seropositive Very Elderly People: Results From the BELFRAIL Study. W Adriaensen, E Derhovanessian, B Vaes, G Van Pottelbergh, JM Degryse, G Pawelec, K Hamprecht, H Theeten, C Matheï. J Gerontol A Biol Sci Med Sci 2015 Feb;70(2):143-154. "In the elderly persons, 7.2% had an inverted CD4:8 ratio, which was associated with CMV seropositivity, less naive, and more late-differentiated CD4+ and CD8+ T cells. However, 32.8% had a CD4:8 ratio >5, a phenotype associated with a higher proportion of naive T cells and absent in young donors. In CMV seropositives, this subgroup had lower proportions of late-differentiated CD4+ and CD8+ T cells and weaker anti-CMV immunoglobulin G reactivity. This novel naive T-cell-dominated phenotype was counterintuitively associated with a higher proportion of those with impaired physical functioning in the very elderly people infected with CMV."

Adriaensen - J Gerontol A Biol Sci Med Sci 2015 abstract / PubMed

CCR4+ Regulatory T Cells Accumulate in the Very Elderly and Correlate With Superior 8-Year Survival. E Derhovanessian, S Chen, AB Maier, K Hähnel, AJ de Craen, H Roelofs, R Westendorp, G Pawelec. J Gerontol A Biol Sci Med Sci 2015 Aug;70(8):917-923. 114 donors aged 18-89. "There were more CCR4+ and CCR4- Tregs in the elderly than the young. Finally, using a subset of 48 elderly donors participating in the Leiden 85-plus study we documented that people with greater median frequencies of CCR4+ Tregs enjoyed a better 8-year survival rate than those with lower frequencies of these cells."

Derhovanessian - J Gerontol A Biol Sci Med Sci 2015 abstract / PubMed

IFNγ-TNFα-IL2-MIP1α-CD107a+PRF1+ CD8 pp65-Specific T-Cell Response Is Independently Associated With Time to Death in Elderly Humans. S Ferrando-Martínez, E Ruiz-Mateos, JP Casazza, RS de Pablo-Bernal, B Dominguez-Molina, MA Muñoz-Fernández, J Delgado, R de la Rosa, R Solana, RA Koup, M Leal. J Gerontol A Biol Sci Med Sci 2015 Oct;70(10):1210-1218. 2-year followup of healthy donors aged over 50 years. "A cytotoxic CD8 pp65-specific T-cell response, without cytokine or chemokine coexpression, was independently associated with all-cause mortality in these elderly individuals."

Ferrando-Martínez - J Gerontol A Biol Sci Med Sci 2014 / PubMed

Cytomegalovirus infection accelerates epigenetic aging. L Kananen, T Nevalainen, J Jylhävä, S Marttila, A Hervonen, M Jylhä, M Hurme. Exp Gerontol 2015 Dec;72:227-229. "[W]e now have analyzed the correlation of CMV seropositivity with the epigenetic age in the Vitality 90 + cohort 1920 (122 nonagenarians and 21 young controls, CMV seropositivity rates 95% and 57%, respectively). The data showed that CMV seropositivity was associated with a higher epigenetic age in both of these age groups (median 26.5 vs. 24.0 (p < 0.02, Mann–Whitney U -test) in the young controls and 76.0 vs. 70.0 (p < 0.01) in the nonagenarians)."

Kananen - Exp Gerontol 2015 abstract / Science Direct

Cytomegalovirus viral load within blood increases markedly in healthy people over the age of 70 years. HM Parry, J Zuo, G Frumento, N Mirajkar, C Inman, E Edwards, M Griffiths, G Pratt, P Moss. Immun Ageing 2016 Jan 5;13:1. "Viral DNA was detected in 24 % (9/37) of donors below the age of 70 but was found in all individuals above this age. Furthermore, the mean CMV load was only 8.6 copies per 10,000 monocytes until approximately 70 years of age when it increased by almost 30 fold to 249 copies in older individuals (p < 0.0001). CMV was found within classical CD14+ monocytes and was not detectable within the CD14-CD16+ subset. The titre of CMV-specific IgG increased inexorably with age indicating that loss of humoral immunity is not a determinant of the increased viral load. In contrast, although cellular immunity to the structural late protein pp65 increased with age, the T cell response to the immediate early protein IE1 decreased in older donors."

Parry - Immun Ageing 2016 full article / PubMed Central
Parry - Immun Ageing 2016 full article

CMV seropositivity and T-cell senescence predict increased cardiovascular mortality in octogenarians: results from the Newcastle 85+ study. I Spyridopoulos, C Martin-Ruiz, C Hilkens, ME Yadegarfar, J Isaacs, C Jagger, T Kirkwood, T von Zglinicki. Aging Cell 2016 Apr;15(2):389-392. 751 octogenarians from the Newcastle 85+ study followed 65 months. "CMV-seropositive participants showed a higher prevalence of CHD (37.7% vs. 26.7%, P = 0.030) compared to CMV-seronegative participants together with lower CD4/CD8 ratio (1.7 vs. 4.1, P < 0.0001) and higher frequencies of senescence-like CD4 memory cells (41.1% vs. 4.5%, P < 0.001) and senescence-like CD8 memory cells (TEMRA, 28.1% vs. 6.7%, P < 0.001). CMV seropositivity was also associated with increased six-year cardiovascular mortality (HR 1.75 [1.09-2.82], P = 0.021) or death from myocardial infarction and stroke (HR 1.89 [107-3.36], P = 0.029)."

Spyridopoulos / Aging Cell 2016 full article

Immunity in young adult survivors of childhood leukemia is more similar to elderly rather than age-matched controls: Role of cytomegalovirus (CMV). MS Azanan, NK Abdullah, LL Chua, SH Lum, SS Ghafar, A Kamarulzaman, S Kamaruzzaman, SR Lewin, YL Woo, H Ariffin, R Rajasuriar. Eur J Immunol 2016 Jul;46(7):1715-1726. "We found that markers of systemic inflammation - IL-6 and human C-reactive protein (hCRP) and immune activation - CD38 and HLA-DR on T cells, sCD163 from monocytes and macrophages - were increased in survivors compared to controls. T-cell responses specific to cytomegalovirus (CMV) were also increased in survivors compared to controls while CMV IgG levels in survivors were comparable to levels measured in the elderly (>50years) and correlated with IL-6, hCRP, sCD163 and CD57+ CD28- memory T cells."

Azanan - Eur J Immunol 2016 abstract / PubMed

Income and Markers of Immunological Cellular Aging. AE Aiello, L Feinstein, JB Dowd, G Pawelec, E Derhovanessian, S Galea, M Uddin, DE Wildman, AM Simanek. Psychosom Med 2016 Jul-Aug;78(6):657-666. 79 individuals in the Detroit Neighborhood Health Study. "After adjustment for age, sex, race, smoking, medication use, and lifetime history of mental health conditions, lower income was associated with a 0.41 (95% confidence interval = 0.09-0.72) log-unit increase in the CD4 E/N ratio and a 0.20 (95% confidence interval = 0.02-0.39) log-unit increase in the CD8 E/N ratio. CMV immunoglobulin G antibody level partially mediated these associations."

Aiello - Psychosom Med 2016 abstract / PubMed

T-Cell Phenotypes Predictive of Frailty and Mortality in Elderly Nursing Home Residents. J Johnstone, R Parsons, F Botelho, J Millar, S McNeil, T Fulop, JE McElhaney, MK Andrew, SD Walter, PJ Devereaux, M Malek, RR Brinkman, J Bramson, M Loeb. J Am Geriatr Soc 2017 Jan;65(1):153-159. 141 deaths among 1072 nursing home residents age 65+. "[H]igher percentages of naïve CD4+ T-cells (P = .001) and effector memory CD8+ T-cells (P = .02) were associated with a lower mean Frailty Index, whereas a higher percentage of CD8+ central memory T-cells was associated with a higher mean Frailty Index score (P = .02).... Multivariable analysis showed a significant negative multiplicative interaction between age and percentage of CMV-reactive CD4+ T-cells (hazard ratio = 0.87, 95% confidence interval = 0.79-0.96). No other significant factors were identified."

Johnstone - J Am Geriatr Soc 2017 abstract / PubMed

CMV induces expansion of highly polyfunctional CD4+ T cell subset coexpressing CD57 and CD154. A Pera, A Vasudev, C Tan, H Kared, R Solana, A Larbi. J Leukoc Biol 2017 Feb;101(2):555-566. "We demonstrate that CD4+ T cells that coexpress CD57 and CD154, which are exclusively present in CMV-positive individuals, are the most polyfunctional CD4+ subset, whereas CD4+CD27+CD28- T cells associate with lower polyfunctionality. Conversely, the frequency of CD4+CD28+ T cells correlates with higher polyfunctionality of CD4+CD57- T cells from CMV-seronegative individuals and CD4+CD57+CD154+ T cells from CMV-seropositive individuals. Thus, polyfunctionality is a property of central memory CD4+ T cells in CMV-seronegative individuals, whereas after CMV infection, polyfunctional T cells become highly differentiated, which allows efficient eradication of infections."

Pera - J Leukoc Biol 2017 abstract / PubMed

Aged-associated cytomegalovirus and Epstein-Barr virus reactivation and cytomegalovirus relationship with the frailty syndrome in older women. RL Thomasini, DS Pereira, FSM Pereira, EC Mateo, TN Mota, GG Guimarães, LSM Pereira, CX Lima, MM Teixeira, AL Teixeira AL Jr. PLoS One 2017 Jul 10;12(7):e0180841. "Among elderly women (n = 71), 59% were positive for CMV, in contrast to only 8% of young women (n = 73). Elderly women classified as frail, pre-frail, and non-frail presented 82%, 56%, and 48% positivity for CMV, respectively. Frequency and viral load were significantly higher in the elderly group vs. the young group (p < 0.0001 and p = 0.01, respectively) and in elderly with frailty vs. those without frailty (p = 0.007 and p = 0.03, respectively). The frequency of CMV reactivation presented odds ratios of 11.77 for aging and 6.13 for frailty, and relative risks of 5.39 for aging and 1.93 for frailty."

Thomasini / PLoS One 2017 full article

Systemic Age-Associated DNA Hypermethylation of ELOVL2 Gene: In Vivo and In Vitro Evidences of a Cell Replication Process. MG Bacalini, J Deelen, C Pirazzini, M De Cecco, C Giuliani, C Lanzarini, F Ravaioli, E Marasco, D van Heemst, HE Suchiman, R Slieker, E Giampieri, R Recchioni, F Mercheselli, S Salvioli, G Vitale, F Olivieri, AM Spijkerman, ME Dollé, JM Sedivy, G Castellani, C Franceschi, PE Slagboom, P Garagnani. J Gerontol A Biol Sci Med Sci 2017 Aug 1;72(8):1015-1023. "Finally we showed that, although the methylation of the two loci is not associated with longevity/mortality in the Leiden Longevity Study, ELOVL2 methylation is associated with cytomegalovirus status in nonagenarians, which could be informative of a higher number of replication events in a fraction of whole-blood cells. Collectively, these results indicate that ELOVL2 methylation is a marker of cell divisions occurring during human aging."

Bacalini - J Gerontol A Biol Sci Med Sci 2017 abstract / PubMed

Persistent Herpesvirus Infections and Telomere Attrition Over 3 Years in the Whitehall II Cohort. JB Dowd, JA Bosch, A Steptoe, B Jayabalasingham, J Lin, R Yolken, AE Aiello. J Infect Dis 2017 Sep 1;216(5):565-572. 400 subjects. "CMV, herpes simplex virus type 1, and human herpesvirus 6 infection were independently associated with greater 3-year LTL attrition, with no association found for Epstein-Barr virus. The magnitudes of these associations were large, for example, the equivalent of almost 12 years of chronological age for those CMV seropositive. Seropositivity to more herpesviruses was additively associated with greater LTL attrition... These associations were robust to adjustment for age, sex, employment grade, body mass index, and smoking status."

Dowd - J Infect Dis 2017 abstract / PubMed

Telomere Shortening, Inflammatory Cytokines, and Anti-Cytomegalovirus Antibody Follow Distinct Age-Associated Trajectories in Humans. A Lustig, HB Liu, EJ Metter, Y An, MA Swaby, P Elango, L Ferrucci, RJ Hodes, NP Weng. Front Immunol 2017 Aug 24;8:1027. 465 subjects. "Our findings thus reveal that age-related trajectories of telomere attrition, elevated circulating inflammatory cytokines, and anti-CMV IgG are independent and that aging individuals do not show a uniform pattern of change in these variables. Immune aging processes are complex and vary across individuals, and the use of multiple biomarkers is essential to evaluation of biological aging of the immune system."

Lustig - Front Immunol 2017 full article / PubMed Central
Lustig / Front Immunol 2017 full article

T Cell Immunosenescence after Early Life Adversity: Association with Cytomegalovirus Infection. MMC Elwenspoek, K Sias, X Hengesch, VK Schaan, FAD Leenen, P Adams, SB Mériaux, S Schmitz, F Bonnemberger, A Ewen, H Schächinger, C Vögele, CP Muller, JD Turner. Front Immunol 2017 Oct 17;8:1263. 18 adoptees, 59 controls. "[W]hen specifically investigating T cells, we found a higher expression of senescence markers (CD57) in ELA. In addition, senescent T cells (CD57+) in ELA had an increased cytolytic potential compared to senescent cells in controls. With a mediation analysis we demonstrated that cytomegalovirus (CMV) infection, which is an important driving force of immunosenescence, largely accounted for elevated CD57 expression observed in ELA."

Elwenspoek - Front Immunol 2017 full article / PubMed Central

CD28null pro-atherogenic CD4 T-cells explain the link between CMV infection and an increased risk of cardiovascular death. A Pera, S Caserta, F Albanese, P Blowers, G Morrow, N Terrazzini, HE Smith, C Rajkumar, B Reus, JR Msonda, M Verboom, M Hallensleben, R Blasczyk, KA Davies, F Kern. Theranostics 2018 Aug 7;8(16):4509-4519. 136 CMV+, 106 CMV-. "Unexpectedly, aging contributed only marginally to an increase in CD28null T-cell frequencies, and only in CMV+ individuals. Interestingly, the presence of HLA-DRB1*0301 led to an approximately 9-fold reduction of the risk of having CD28null CD4 T-cell expansions (OR=0.108, p=0.003). Over 75% of CMV-reactive CD4 T-cells were CD28null."

Pera / Theranostics 2018 full article
Pera - Theranostics 2018 full article / PubMed Central

Association of epigenetic age and p16INK4a with markers of T cell composition in a healthy cohort. CE Burd, J Peng, BF Laskowski, JL Hollyfield, S Zhang, P Fadda, L Yu, RR Andridge, JK Kiecolt-Glaser. J Gerontol A Biol Sci Med Sci 2020 May 3 [Epub ahead of print]. 117 healthy couples age 21-72. "DNAm [Horvath epigenetic clock] measurements correlated with CMV seropositivity as well as PBTL mRNAs indicative of effector function (CD8A, EOMES, TBX21, GZMB), poor proliferative capacity (KLRG1, CD57), differentiation (CD45RO, CD45RA) and immune checkpoints (PDCD1, TIGIT, LAG3, CD160, CD244)."

Burd - J Gerontol A Biol Sci Med Sci 2020 abstract / PubMed

Limited effect of duration of CMV infection on adaptive immunity and frailty: insights from a 27-year-long longitudinal study. LD Samson, SP van den Berg, P Engelfriet, AM Boots, M Hendriks, LG de Rond, ML de Zeeuw-Brouwer, WM Verschuren, JA Borghans, AM Buisman, D van Baarle. Clin Transl Immunology 2020 Oct 14;9(10):e1193. 268 subjects, 136 were long-term and 19 seroconverted. "No clear association between duration of CMV infection and the size and function of the memory T-cell pool was observed. Elevated CMV-specific antibody levels were associated with the prevalence of cardiovascular disease but not with frailty."

Samson - Clin Transl Immunology 2020 full article / PubMed Central

CMV Causes Mental Decline

Impact of viral and bacterial burden on cognitive impairment in elderly persons with cardiovascular diseases. SE Strandberg, KH Pitkala, KH Linnavuori, RS Tilvis. Stroke 2003 Sep;34(9):2126-2131. Among 383 home-dwelling elderly with cardiovascular diseases (mean age, 80 years): "At baseline, 58 individuals (15.1%) had cognitive impairment, which after adjustments was significantly associated with seropositivity for 3 viruses (hazard ratio, 2.5; 95% CI, 1.3 to 4.7). MMSE score decreased in 150 (43% of 348) during 12-month follow-up. After adjustment for MMSE score at baseline and with 0 to 1 seropositivities as reference (1.0), the hazard ratios were 1.8 (95% CI, 0.9 to 3.6) and 2.3 (95% CI, 1.1 to 5.0) for 2 and 3 seropositivities, respectively. The prevalence of possible or definite dementia according to CDR also increased with viral burden. No significant associations were observed between bacterial burden and cognition." They noted that "all our study participants had some kind of atherosclerotic disease at baseline, which may attenuate the observed association between infection and cognitive impairment."

Strandberg - Stroke 2003 abstract / PubMed
Strandberg / Stroke 2003 full article

Immune consequences of the spontaneous pro-inflammatory status in depressed elderly patients. P Trzonkowski, J Myśliwska, B Godlewska, E Szmit, K Łukaszuk, J Wieckiewicz, L Brydak, M Machała, J Landowski, A Myśliwski. Brain Behav Immun 2004 Mar;18(2):135-148. 10 elderly depressed patients and 10 controls. "Higher levels of anti-CMV, higher percentage of the CD28- CD57+ cells, and elevated levels of TNFalpha, IL6, and cortisol concomitant with decreased levels of ACTH and insufficient production of IL10 (which increased the IFNgamma+ /IL10+ ratio) were found in the patients suffering from depression, in comparison to healthy controls. The subjects with depression revealed a low NK cytotoxicity, while a level of CD3+ CD8+ IFNgamma+ cells was comparable between the groups."

Trzonkowski - Brain Behav Immun 2004 abstract / PubMed

The influence of latent viral infection on rate of cognitive decline over 4 years. AE Aiello, M Haan, L Blythe, K Moore, JM Gonzalez, W Jagust. J Am Geriatr Soc 2006 Jul;54(7):1046-1054. In 1204 community-dwelling elderly aged 60 to 100, "[t]here was a significantly higher rate of cognitive decline over the 4-year period in subjects with the highest CMV antibody levels at baseline than in individuals with the lowest levels (beta=-0.053, standard error =0.018; P=.003), after controlling for age, sex, education, income, and chronic health conditions. There was no association between HSV-1 antibody levels and cognitive decline. CRP did not modify the relationship between viral antibody levels and cognitive decline."

Aiello - J Am Geriatr Soc 2006 abstract / PubMed

Decreased proportion of cytomegalovirus specific CD8 T-cells but no signs of general immunosenescence in Alzheimer's disease. G Westman, AK Lidehall, P Magnusson, M Ingelsson, L Kilander, L Lannfelt, O Korsgren, BM Eriksson. PLoS One 2013 Oct 14;8(10):e77921. 50 AD patients, 50 controls. "Among CMV seropositive subjects, patients with AD had significantly lower proportions of CMV-specific CD8 T-cells compared to controls, 1.16 % vs. 4.13 % (p=0.0057). Regardless of dementia status, CMV seropositive subjects presented with a lower proportion of naïve CD8 cells and a higher proportion of effector CD8 cells compared to seronegative subjects."

Westman - PLoS One 2013 full article / PubMed Central
Westman / PLoS One 2013 full article

The Inverted CD4:CD8 Ratio Is Associated with Cytomegalovirus, Poor Cognitive and Functional States in Older Adults. B Luz Correa, AP Ornaghi, G Cerutti Muller, P Engroff, R Pestana Lopes, I Gomes da Silva Filho, JA Bosch, C Bonorino, ME Bauer. Neuroimmunomodulation 2014;21(4):206-212. 360 subjects. "Fifty-nine individuals were identified with CD4:CD8 ratio <1, and had increased IgG titers to CMV (p < 0.01), but not to EBV, compared to subjects with CD4:CD8 ratio >1. The older adults with inverted CD4:CD8 ratio had impairments in some cognitive dimensions and had more functional disability and dependency (p = 0.01) than subjects with CD4:CD8 ratio >1... The increased CMV-IgG titers alone contributed to 8× higher chance to invert CD4:CD8 T cell ratio (OR 8.12, 95% CI 1.74-37.88, p < 0.01)."

Luz Correa - Neuroimmunomodulation 2014 abstract / PubMed

Association between Cytomegalovirus Antibody Levels and Cognitive Functioning in Non-Elderly Adults. F Dickerson, C Stallings, A Origoni, E Katsafanas, LA Schweinfurth, CL Savage, R Yolken. PLoS One 2014 May 20;9(5):e95510. 521 subjects. "There was an incremental relationship between the level of CMV antibody elevation and the odds of a low RBANS Total score. The odds of a low total cognitive score were 1.63 (95th % CI 1.01, 2.64; p<.045), 2.22 (95th % CI 1.33, 3.70; p<.002), and 2.46 (95th % CI 1.24, 4.86; p<.010) with a CMV antibody level greater than or equal to the 50th, 75th, and 90th percentile respectively."

Dickerson - PLoS One 2014 full article / PubMed Central
Dickerson - PLoS One 2014 full article

Monocyte Phenotype and Polyfunctionality Are Associated With Elevated Soluble Inflammatory Markers, Cytomegalovirus Infection, and Functional and Cognitive Decline in Elderly Adults. RS de Pablo-Bernal, J Cañizares, I Rosado, MI Galvá, AI Alvarez-Ríos, A Carrillo-Vico, S Ferrando-Martínez, MÁ Muñoz-Fernández, M Rafii-El-Idrissi Benhnia, YM Pacheco, R Ramos, M Leal, E Ruiz-Mateos. J Gerontol A Biol Sci Med Sci 2016 May;71(5):610-618. 20 elderly adults, 20 young controls. "The activation phenotype was independently associated with the anti-cytomegalovirus IgG levels and with functional and cognitive decline. These data demonstrate that monocytes are key cell candidates for the source of the high soluble inflammatory levels. Our findings suggest that cytomegalovirus infection might be a driving force in the activation of monocytes and is associated with the functional and cognitive decline."

de Pablo-Bernal - J Gerontol A Biol Sci Med Sci 2016 abstract / PubMed

Temporal Cognitive Decline Associated With Exposure to Infectious Agents in a Population-based, Aging Cohort. VL Nimgaonkar, RH Yolken, T Wang, HC Chung-Chou, L McClain, E McDade, BE Snitz, M Ganguli. Alzheimer Dis Assoc Disord 2016 Jul-Sep;30(3):216-222. 5 year followup. "The IgG levels for HSV-2 were significantly associated with baseline cognitive domain scores (N=1022 participants). Further, the IgG levels for HSV-2, TOX, and CMV, but not HSV-1 were significantly associated with greater temporal cognitive decline that varied by type of infection."

Nimgaonkar - Alzheimer Dis Assoc Disord 2016 abstract / PubMed

Association of cytomegalovirus and Epstein-Barr virus with cognitive functioning and risk of dementia in the general population: 11-year follow-up study. M Torniainen-Holm, J Suvisaari, M Lindgren, T Härkänen, F Dickerson, RH Yolken. Brain Behav Immun 2018 Mar;69:480-485. In 7112 Finnish adults, "Seropositivity did not predict dementia diagnosis."

Torniainen-Holm - Brain Behav Immun 2018 abstract / PubMed

Immune Response to Cytomegalovirus and Cognition in the Health and Retirement Study. RC Stebbins, GA Noppert, YC Yang, JB Dowd, A Simanek, AE Aiello. Am J Epidemiol 2020 Oct 23:kwaa238 [epub ahead of print]. 5617 subjects. "Overall, both CMV seropositivity and higher IgG were associated with lower cognitive function, though the relationship was not statistically significant in adjusted models."

Stebbins - Am J Epidemiol 2020 abstract / PubMed

CMV and Infections in Children

Role of cytomegalovirus infection in the incidence of viral acute respiratory infections in children attending day-care centers. JJ Chomel, JP Allard, D Floret, D Honneger, L David, B Lina, M Aymard. Eur J Clin Microbiol Infect Dis 2001 Mar;20(3):167-172. "The percentage of children becoming CMV positive was significantly (P<0.001) higher in day-care centers where more than 40 children were enrolled. Nine outbreaks due to respiratory syncytial virus, rhinovirus and enterovirus were recorded in 8 of 29 (27.6%) day-care centers. Viral acute respiratory infections were significantly (P<0.05) more frequently recorded in day-care centers in which CMV and respiratory viruses cocirculated and were significantly (P<0.001) more frequently reported in CMV-infected children."

Chomel - Eur J Clin Microbiol Infect Dis 2001 abstract / PubMed

Deliberate anti-smoker scientific fraud: Charlatans exploit socioeconomic differences in CMV infection to falsely blame passive smoking:

Effects of parental smoking on interferon {gamma} production in children. G Tebow, DL Sherrill, IC Lohman, DA Stern, AL Wright, FD Martinez, M Halonen, and S Guerra. Pediatrics 2008 Jun;121(6):e1563-e1569. While purposely ignoring the fact that cytomegalovirus infection reduces IFN-gamma responses, and the fact that, for socioeconomic reasons, smokers and passive smokers (and their children) are more likely to have been infected by CMV, these criminals falsely pretended that passive smoking causes "impairment of the immune system function." This bogus study was undoubtably concocted for use in Surgeon General reports, which have always systematically ignored the role of infection in a multitude of diseases in order to falsely blame smoking. The SG reports are instigated by politicians, and their corrupt authors are never subjected to scientific scrutiny!

Tebow / Pediatrics 2008 abstract

Cytomegalovirus infection induces T-cell differentiation without impairing antigen-specific responses in Gambian infants. DJ Miles, M Sanneh, B Holder, S Crozier, S Nyamweya, ES Touray, MS Palmero, SM Zaman, S Rowland-Jones, M van der Sande, H Whittle. Immunology 2008 Jul;124(3):388-400. "While the concentration of undifferentiated (CD27(+) CD28(+) CCR7(+)) T-cells in peripheral blood was unaffected by CMV, there was a large increase in differentiated (CD28(-) CD57(+)) CD8 T-cells and a smaller increase in differentiated CD4 cells. One week post-vaccination, the CD4 cell interferon-gamma (IFN-gamma) response to measles was lower among CMV-infected infants, but there were no other differences between the cytokine responses, or between the cytokine or proliferative responses 4 months post-vaccination."

Miles - Immunology 2008 abstract / PubMed
Miles - Immunology 2008 full article / PubMed Central

Herpesvirus seropositivity in childhood associates with decreased monocyte-induced NK cell IFN-gamma production. S Saghafian-Hedengren, Y Sundström, E Sohlberg, C Nilsson, A Linde, M Troye-Blomberg, L Berg, E Sverremark-Ekström. J Immunol 2009 Feb 15;182(4):2511-2517. "SP children had a significantly reduced proportion of IFN-gamma(+) NK cells and cognate intracellular IFN-gamma levels, which was more pronounced in CMV-coinfected subjects. Also, resting PBMCs of SP children displayed lower proportions of proinflammatory monocytes. IFN-gamma production by NK cells was dependent on interactions with monocytes, with the proinflammatory subset inducing the highest IFN-gamma. Finally, SP children had markedly lower levels of plasma IFN-gamma, concurrent with in vitro findings."

Saghafian-Hedengren / J Immunol 2009 full article

Human cytomegalovirus infant infection adversely affects growth and development in maternally HIV-exposed and unexposed infants in Zambia. UA Gompels, N Larke, M Sanz-Ramos, M Bates, K Musonda, D Manno, J Siame, M Monze, S Filteau; CIGNIS Study Group. Clin Infect Dis 2012 Feb 1;54(3):434-442. 811 infants from a double-blind, randomized controlled trial of micronutrient-fortified infant foods. "All HCMV-seropositive infants had decreased length-for-age by 18 months compared with seronegative infants (standard deviation [z]-score difference: -0.44 [95% confidence interval {CI}, -.72 to -.17]; P = .002). In HIV-exposed infants, those who were HCMV positive compared with those who were negative, also had reduced head size (mean z-score difference: -0.72 [95% CI, -1.23 to -.22]; P = .01) and lower psychomotor development (Bayley test score difference: -4.1 [95% CI, -7.8 to -.5]; P = .03). HIV-exposed, HCMV-viremic infants were more commonly referred for hospital treatment than HCMV-negative infants. The effects of HCMV were unaffected by micronutrient fortification."

Gompels - Clin Infect Dis 2012 full article / PubMed Central

Cytomegalovirus-specific CD4 and CD8 T cell responses in infants and children. AK Lidehäll, ML Engman, F Sund, G Malm, I Lewensohn-Fuchs, U Ewald, TH Tötterman, E Karltorp, O Korsgren, BM Eriksson. Scand J Immunol 2013 Feb;77(2):135-143. 24 children with congenital CMV infection, 19 children with postnatal CMV infection and eight adults with primary CMV infection. "Our results show that whereas adults display high CMV-specific CD4 T cell responses in the initial phase of the infection, children younger than 2 years have low or undetectable responses that appear to increase with time. There were no differences between groups with regard to CD8 T cell function."

Lidehäll - Scand J Immunol 2013 abstract / PubMed

Epstein-Barr Virus Co-infection in Children Boosts Cytomegalovirus-induced Differentiation of Natural Killer Cells. S Saghafian-Hedengren, E Sohlberg, J Theorell, C Carvalho-Queiroz, N Nagy, JO Persson, C Nilsson, YT Bryceson, E Sverremark-Ekström. J Virol. 2013 Dec;87(24):13446-13455. "Co-infected children had significantly higher proportions of peripheral-blood NKG2C+ NK cells than CMV+EBV- children. Ex vivo NK-cell degranulation after target cell stimulation and plasma IL-15 levels were significantly higher in CMV+ children. EBV co-infection related with the highest levels of plasma IL-15 and IL-12p70. Remarkably, in vitro EBV infection of peripheral blood mononuclear cells (PBMC) from EBV-CMV+ children increased NKG2C+ NK-cell proportions..."

Saghafian-Hedengren - J Virol 2013 abstract / PubMed

Cutting Edge: NKG2ChiCD57+ NK Cells Respond Specifically to Acute Infection with Cytomegalovirus and Not Epstein-Barr Virus. DW Hendricks, HH Balfour Jr, SK Dunmire, DO Schmeling, KA Hogquist, LL Lanier. J Immunol 2014 May 15;192(10):4492-4496. "We describe a longitudinal study of CMV(-) and CMV(+) students who were acutely infected with EBV. The NKG2C(hi) NK subset was not expanded by EBV infection. However, EBV infection caused a decrease in the absolute number of immature CD56(bright)CD16(-) NK cells in the blood and, in CMV(+) individuals, induced an increased frequency of mature CD56(dim)NKG2A(+)CD57(+) NK cells in the blood that persisted into latency. These results provide further evidence that NKG2C(+) NK cells are CMV specific and suggest that EBV infection alters the repertoire of NK cells in the blood."

Hendricks - J Immunol 2014 abstract / PubMed

Human Cytomegalovirus Modulates Monocyte-Mediated Innate Immune Responses during Short-Term Experimental Latency In Vitro. VM Noriega, KK Haye, TA Kraus, SR Kowalsky, Y Ge, TM Moran, D Tortorella. J Virol 2014 Aug 15;88(16):9391-9405. "Infection of CD14+ monocytes by HCMV results in the generation of latency-specific transcripts, maintenance of viral genomes, and the capacity to reenter the lytic cycle. During short-term latency in monocytes the virus initiates a program of differentiation to inflammatory macrophages that coincides with the modulation of cytokine secretion and specific cellular processes. HCMV-infected monocytes are hindered in their capacity to exert normal immunoprotective mechanisms. Additionally, latent virus disrupts type I and II interferon signaling at the level of STAT1 phosphorylation."

Noriega - J Virol 2014 abstract / PubMed

CMV- and EBV-induced T-cell expansions in young children do not impair naive T-cell populations or vaccination responses. The Generation R Study. D van den Heuvel, MA Jansen, WA Dik, H Bouallouch-Charif, D Zhao, KA van Kester, MA Smits-Te Nijenhuis, MJ Kolijn-Couwenberg, VW Jaddoe, R Arens, JJ van Dongen, HA Moll, MC van Zelm. J Infect Dis 2016 Jan 15;213(2):233-242. "CMV and EBV infections were associated with significant expansions of CD27- and CD27+ effector memory T cells, respectively. These expansions were enhanced in CMV+EBV+ children and were independent of VZV or HSV-1 co-infection. Naive and central memory T-cell numbers were not affected, nor were anti-tetanus and anti-measles IgG levels. Children infected before 2y of age showed smaller effector memory T-cell expansions than children infected between 2-6y."

van den Heuvel - J Infect Dis 2016 abstract / PubMed

Effects of nongenetic factors on immune cell dynamics in early childhood: The Generation R Study. EG Lochem, LE Bakker-Jonges, H Bouallouch-Charif, VW Jaddoe, H Hooijkaas, JJ van Dongen, HA Moll, MC van Zelm. J Allergy Clin Immunol 2017 Jun;139(6):1923-1934.e17. 1,182 children from birth to age 6. "Dynamics of CD4+ T cells were predominantly associated with gender, birth characteristics, and persistent infections with cytomegalovirus (CMV) or Epstein Barr virus (EBV). CD8+ T cells were predominantly associated with CMV and EBV infections, and TCRγδ+ T cells with premature rupture of membranes and CMV infection."

Lochem - J Allergy Clin Immunol 2017 abstract / PubMed

See Also:

CMV and Social Class
CMV & other infections cause heart disease
The Surgeon General Lies That Smoking Causes Heart Disease
CMV Causes Rheumatoid Arthritis
CMV is Implicated in Leukemia
Infections Cause Hearing Loss [CMV]
Infections Cause Diabetes [CMV]
Influenza Causes Deaths From Heart and Respiratory Disease [CMV]


cast 11-12-20

cast 12-10-12