Paring Down Cytomegalovirus’s Role in Acute Respiratory Distress Syndrome Outcome* Jeffery L. Meier, MD Division of Infectious Diseases Department of Internal Medicine Carver College of Medicine University of Iowa; and Iowa City Veterans Affairs Healthcare System Iowa City, IA
C
ytomegalovirus (CMV) is part of the virome in over half of the adult population, with a prevalence that varies by age, race/ethnicity, and socioeconomic factors. This human-specific herpesvirus sits silently in wait to reactivate upon stimulation by what appears to be inordinate levels of inflammatory mediators or stress. CMV reactivation is normally squelched by innate and adaptive immune responses, but frequently generates waves of viral replication when this immunity weakens. Unrestrained CMV replication can attain levels that directly damage tissues and produce a characteristic spectrum of clinical disease. Less clear are the out of the ordinary clinical consequences of smoldering CMV replication that may emanate from various tissue compartments or sanctuary sites and sometimes manifest as low-level CMV DNAemia or antigenemia. Within this realm of uncertainty falls the relationship of CMV reactivation and disease in previously nonimmunocompromised persons having critical illness. Remarkably, CMV DNAemia develops in up to one third of ICU patients with protracted critical illness, ostensibly reflecting high-level severity of the underlying acute inflammation and injury in conjunction with the ensuing immunosuppression, especially accompanying severe sepsis. CMV is not unique in this regard, as high reactivation rates of herpes simplex virus and human herpes virus 6 are also observed, and often register as viral DNAemia (1). Time *See also p. 394. Key Words: acute lung injury; acute respiratory distress syndrome; cytomegalovirus Dr. Meier is employed by the University of Iowa and Veterans Affairs, has received support for article research from the Department of Veterans Affairs (funded his effort), and has disclosed government work. His institution received grant support from VIIV Healthcare/GlaxoSmithKline, Chimerix, Sanofi Pasteur, Pfizer, Serono Labs, Cubist, and N01AI0800008 National Institutes of Health/National Institute of Allergy and Infectious Diseases/Division of Microbiology and Infectious Diseases—Vaccine Treatment Evaluation Unit (support for clinical research unrelated to the work under consideration), and his institution received grant support from the Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, and Biomedical Laboratory Research and Development 1BX001107-01. He received support for the development of educational presentations from Health Resources and Services Administration/AIDS Education and Training Centers (H4AHA00062) (Midwest AIDS Education and Training Center of Iowa). Copyright © 2015 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins DOI: 10.1097/CCM.0000000000000828
498
www.ccmjournal.org
to first detection of CMV replication generally lags behind that of HSV, and both viruses are also commonly detected in respiratory fluid of critically ill patients. Meta-analysis of pooled results from over a dozen of clinical studies indicates that active CMV infection in nonimmunosuppressed ICU patients is associated with prolonged mechanical ventilation, prolonged hospital and ICU stay, and higher mortality (2). CMV DNAemia or antigenemia occurs with greater frequency in association with prolonged ICU stay (> 4 d), severe sepsis/septic shock, and high severity of illness. Higher levels of plasma CMV DNAemia are associated with higher risk of prolonged hospitalization or death (3, 4). These collective results prompted some experts to call for a pharmacologic prevention study to directly address the question of whether active CMV infection is a marker versus driver of disease in critically ill nonimmunocompromised CMV-seropositive persons. As an initial step in this direction, a phase II multicenter randomized double-blind, placebo-controlled clinical trial (NCT01335932) was initiated to evaluate whether ganciclovir/valganciclovir prophylaxis reduces serum interleukin-6 levels in CMV-seropositive adults with severe sepsis or trauma associated with acute lung injury (ALI) and respiratory failure, with secondary measures of virologic activity, levels of cytokines in serum and bronchoalveolar lavage fluid, and clinical outcomes. Although the field awaits the results of the antiviral prophylaxis study in CMV-seropositive ICU patients with ALI, the report by Ong et al (5) in this issue of Critical Care Medicine provides us with an additional reality check. In a prospective cohort study of 306 patients in mixed ICUs at two referral centers, the investigators evaluated whether CMV IgG seropositivity (68% of patients) is linked to worse outcome in ICU patients with acute respiratory distress syndrome (ARDS) and requiring mechanical ventilation for at least 4 days. This is a reasonable approach to answering a practical question with pragmatic clinical care implications. Some prior studies in other nonimmunocompromised populations have epidemiologically linked CMV IgG seropositivity with cardiovascular disease, increased all-cause mortality, frailty, and Alzheimer dementia/neurocognitive decline (6–10). In HIV-positive persons, CMV is associated with non-AIDS morbidity and mortality that is possibly linked mechanistically to CMV-mediated immune activation and enhancement of proinflammatory cytokine production (11, 12). Additional CMV reactivation episodes also likely go unnoticed in critically ill previously nonimmunocompromised persons with ARDS despite periodic monitoring for CMV DNAemia, and these too may shape innate and adaptive immunologic responses. Discordant findings of CMV DNA in alveolar fluid and not in blood are common in ICU patients (4, 13, 14). In the mouse CMV model, the latent viral DNA load is highest in lung tissue, and higher levels of latent viral DNA load are associated with higher frequencies of viral reactivation (15). February 2015 • Volume 43 • Number 2
Editorials
Thus, it is conceivable that CMV IgG seropositivity, irrespective of detectable levels of CMV DNAemia or antigenemia, might influence clinical outcome in ICU patients with ARDS. After carefully adjusting for confounding, Ong et al (5) determined that CMV seroprevalence is not associated with either the primary composite outcome measure of number of days alive and free of mechanical ventilation or the separate components of this composite. As they acknowledged, the study is underpowered to detect small differences (< 9% between the three levels of the primary outcome) that could be meaningful. The 26% of CMV-seropositive patients developing CMV DNAemia (> 100 IU/mL) is not as high as the percent of seropositive patients developing viremia in some other ICU studies, and having a higher proportion of patients with CMV DNAemia may expose an outcome difference between CMV-seropositive and CMV-seronegative groups. However, the measured 26% is within range of the proportion of viremic patients reported across a variety of studies, differing by design, assays, and population heterogeneity. Their results in patients with ARDS extend previous findings by De Vlieger et al (16), who showed in a single-center retrospective study that serostatus alone is not a risk factor for worse outcome in a general ICU population. Although higher CMV IgG titers are known to be a risk factor for various diseases in other patient populations, the determination of such titers at several days after the patients presented with critical illness in this study would be problematic for interpretation and, from a practical standpoint, would be subject to inter- and intra-assay variability if applied real time in clinical care. Putting these caveats aside, CMV seropositivity alone cannot be used as a reliable predictor of worse outcome in unselected critically ill patients with ARDS and prolonged mechanical ventilation. Presumably, this group of 209 CMV-seropositive ICU patients with ARDS would not discernibly benefit as a whole from ganciclovir prophylaxis, compared with the CMV-seronegative group, and the drug may do harm. The possibility that a small subset of patients would benefit is not excluded. In post hoc subgroup analyses, CMV-seropositive patients in whom ARDS had developed in a setting of septic shock were at significant risk of worse outcome, compared with CMV-seronegative patients. Although this result requires validation, it suggests that identifying a set of distinct clinical predictors is useful in selecting CMV-seropositive patients at highest risk for worse outcome. A combination of clinical predictors, biomarkers, and immunologic correlates might allow
Critical Care Medicine
for improvement in stratifying highest at-risk patients for feasibility of an antiviral prophylaxis trial for clinical efficacy.
REFERENCES
1. Walton AH, Muenzer JT, Rasche D, et al: Reactivation of multiple viruses in patients with sepsis. PLoS One 2014; 9:e98819 2. Kalil AC, Florescu DF: Prevalence and mortality associated with cytomegalovirus infection in nonimmunosuppressed patients in the intensive care unit. Crit Care Med 2009; 37:2350–2358 3. Limaye AP, Kirby KA, Rubenfeld GD, et al: Cytomegalovirus reactivation in critically ill immunocompetent patients. JAMA 2008; 300:413–422 4. Heininger A, Haeberle H, Fischer I, et al: Cytomegalovirus reactivation and associated outcome of critically ill patients with severe sepsis. Crit Care 2011; 15:R77 5. Ong DSY, Klein Klouwenberg PMC, Verduyn Lunel FM, et al: Cytomegalovirus Seroprevalence as a Risk Factor for Poor Outcome in Acute Respiratory Distress Syndrome. Crit Care Med 2015; 43:394–400 6. Simanek AM, Dowd JB, Pawelec G, et al: Seropositivity to cytomegalovirus, inflammation, all-cause and cardiovascular disease-related mortality in the United States. PLoS One 2011; 6:e16103 7. Schmaltz HN, Fried LP, Xue QL, et al: Chronic cytomegalovirus infection and inflammation are associated with prevalent frailty in community-dwelling older women. J Am Geriatr Soc 2005; 53:747–754 8. Muhlestein JB, Horne BD, Carlquist JF, et al: Cytomegalovirus seropositivity and C-reactive protein have independent and combined predictive value for mortality in patients with angiographically demonstrated coronary artery disease. Circulation 2000; 102:1917–1923 9. Grahame-Clarke C, Chan NN, Andrew D, et al: Human cytomegalovirus seropositivity is associated with impaired vascular function. Circulation 2003; 108:678–683 10. Barnes LL, Capuano AW, Aiello AE, et al: Cytomegalovirus infection and risk of Alzheimer disease in older black and white individuals. J Infect Dis 2014 Aug 8. [Epub ahead of print] 11. Lichtner M, Cicconi P, Vita S, et al: Cytomegalovirus coinfection is associated with an increased risk of severe non-AIDS-defining events in a large cohort of HIV-infected patients. J Infect Dis 2014 Jul 31. [Epub ahead of print] 12. Hunt PW, Martin JN, Sinclair E, et al: Valganciclovir reduces T cell activation in HIV-infected individuals with incomplete CD4+ T cell recovery on antiretroviral therapy. J Infect Dis 2011; 203:1474–1483 13. Chilet M, Aguilar G, Benet I, et al: Virological and immunological features of active cytomegalovirus infection in nonimmunosuppressed patients in a surgical and trauma intensive care unit. J Med Virol 2010; 82:1384–1391 14. Chiche L, Forel JM, Roch A, et al: Active cytomegalovirus infection is common in mechanically ventilated medical intensive care unit patients. Crit Care Med 2009; 37:1850–1857 15. Reddehase MJ, Podlech J, Grzimek NK: Mouse models of cytomegalovirus latency: Overview. J Clin Virol 2002; 25(Suppl 2):S23–S36 16. De Vlieger G, Meersseman W, Lagrou K, et al: Cytomegalovirus serostatus and outcome in nonimmunocompromised critically ill patients. Crit Care Med 2012; 40:36–42
www.ccmjournal.org
499
Copyright of Critical Care Medicine is the property of Lippincott Williams & Wilkins and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
C
ytomegalovirus (CMV) is part of the virome in over half of the adult population, with a prevalence that varies by age, race/ethnicity, and socioeconomic factors. This human-specific herpesvirus sits silently in wait to reactivate upon stimulation by what appears to be inordinate levels of inflammatory mediators or stress. CMV reactivation is normally squelched by innate and adaptive immune responses, but frequently generates waves of viral replication when this immunity weakens. Unrestrained CMV replication can attain levels that directly damage tissues and produce a characteristic spectrum of clinical disease. Less clear are the out of the ordinary clinical consequences of smoldering CMV replication that may emanate from various tissue compartments or sanctuary sites and sometimes manifest as low-level CMV DNAemia or antigenemia. Within this realm of uncertainty falls the relationship of CMV reactivation and disease in previously nonimmunocompromised persons having critical illness. Remarkably, CMV DNAemia develops in up to one third of ICU patients with protracted critical illness, ostensibly reflecting high-level severity of the underlying acute inflammation and injury in conjunction with the ensuing immunosuppression, especially accompanying severe sepsis. CMV is not unique in this regard, as high reactivation rates of herpes simplex virus and human herpes virus 6 are also observed, and often register as viral DNAemia (1). Time *See also p. 394. Key Words: acute lung injury; acute respiratory distress syndrome; cytomegalovirus Dr. Meier is employed by the University of Iowa and Veterans Affairs, has received support for article research from the Department of Veterans Affairs (funded his effort), and has disclosed government work. His institution received grant support from VIIV Healthcare/GlaxoSmithKline, Chimerix, Sanofi Pasteur, Pfizer, Serono Labs, Cubist, and N01AI0800008 National Institutes of Health/National Institute of Allergy and Infectious Diseases/Division of Microbiology and Infectious Diseases—Vaccine Treatment Evaluation Unit (support for clinical research unrelated to the work under consideration), and his institution received grant support from the Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, and Biomedical Laboratory Research and Development 1BX001107-01. He received support for the development of educational presentations from Health Resources and Services Administration/AIDS Education and Training Centers (H4AHA00062) (Midwest AIDS Education and Training Center of Iowa). Copyright © 2015 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins DOI: 10.1097/CCM.0000000000000828
498
www.ccmjournal.org
to first detection of CMV replication generally lags behind that of HSV, and both viruses are also commonly detected in respiratory fluid of critically ill patients. Meta-analysis of pooled results from over a dozen of clinical studies indicates that active CMV infection in nonimmunosuppressed ICU patients is associated with prolonged mechanical ventilation, prolonged hospital and ICU stay, and higher mortality (2). CMV DNAemia or antigenemia occurs with greater frequency in association with prolonged ICU stay (> 4 d), severe sepsis/septic shock, and high severity of illness. Higher levels of plasma CMV DNAemia are associated with higher risk of prolonged hospitalization or death (3, 4). These collective results prompted some experts to call for a pharmacologic prevention study to directly address the question of whether active CMV infection is a marker versus driver of disease in critically ill nonimmunocompromised CMV-seropositive persons. As an initial step in this direction, a phase II multicenter randomized double-blind, placebo-controlled clinical trial (NCT01335932) was initiated to evaluate whether ganciclovir/valganciclovir prophylaxis reduces serum interleukin-6 levels in CMV-seropositive adults with severe sepsis or trauma associated with acute lung injury (ALI) and respiratory failure, with secondary measures of virologic activity, levels of cytokines in serum and bronchoalveolar lavage fluid, and clinical outcomes. Although the field awaits the results of the antiviral prophylaxis study in CMV-seropositive ICU patients with ALI, the report by Ong et al (5) in this issue of Critical Care Medicine provides us with an additional reality check. In a prospective cohort study of 306 patients in mixed ICUs at two referral centers, the investigators evaluated whether CMV IgG seropositivity (68% of patients) is linked to worse outcome in ICU patients with acute respiratory distress syndrome (ARDS) and requiring mechanical ventilation for at least 4 days. This is a reasonable approach to answering a practical question with pragmatic clinical care implications. Some prior studies in other nonimmunocompromised populations have epidemiologically linked CMV IgG seropositivity with cardiovascular disease, increased all-cause mortality, frailty, and Alzheimer dementia/neurocognitive decline (6–10). In HIV-positive persons, CMV is associated with non-AIDS morbidity and mortality that is possibly linked mechanistically to CMV-mediated immune activation and enhancement of proinflammatory cytokine production (11, 12). Additional CMV reactivation episodes also likely go unnoticed in critically ill previously nonimmunocompromised persons with ARDS despite periodic monitoring for CMV DNAemia, and these too may shape innate and adaptive immunologic responses. Discordant findings of CMV DNA in alveolar fluid and not in blood are common in ICU patients (4, 13, 14). In the mouse CMV model, the latent viral DNA load is highest in lung tissue, and higher levels of latent viral DNA load are associated with higher frequencies of viral reactivation (15). February 2015 • Volume 43 • Number 2
Editorials
Thus, it is conceivable that CMV IgG seropositivity, irrespective of detectable levels of CMV DNAemia or antigenemia, might influence clinical outcome in ICU patients with ARDS. After carefully adjusting for confounding, Ong et al (5) determined that CMV seroprevalence is not associated with either the primary composite outcome measure of number of days alive and free of mechanical ventilation or the separate components of this composite. As they acknowledged, the study is underpowered to detect small differences (< 9% between the three levels of the primary outcome) that could be meaningful. The 26% of CMV-seropositive patients developing CMV DNAemia (> 100 IU/mL) is not as high as the percent of seropositive patients developing viremia in some other ICU studies, and having a higher proportion of patients with CMV DNAemia may expose an outcome difference between CMV-seropositive and CMV-seronegative groups. However, the measured 26% is within range of the proportion of viremic patients reported across a variety of studies, differing by design, assays, and population heterogeneity. Their results in patients with ARDS extend previous findings by De Vlieger et al (16), who showed in a single-center retrospective study that serostatus alone is not a risk factor for worse outcome in a general ICU population. Although higher CMV IgG titers are known to be a risk factor for various diseases in other patient populations, the determination of such titers at several days after the patients presented with critical illness in this study would be problematic for interpretation and, from a practical standpoint, would be subject to inter- and intra-assay variability if applied real time in clinical care. Putting these caveats aside, CMV seropositivity alone cannot be used as a reliable predictor of worse outcome in unselected critically ill patients with ARDS and prolonged mechanical ventilation. Presumably, this group of 209 CMV-seropositive ICU patients with ARDS would not discernibly benefit as a whole from ganciclovir prophylaxis, compared with the CMV-seronegative group, and the drug may do harm. The possibility that a small subset of patients would benefit is not excluded. In post hoc subgroup analyses, CMV-seropositive patients in whom ARDS had developed in a setting of septic shock were at significant risk of worse outcome, compared with CMV-seronegative patients. Although this result requires validation, it suggests that identifying a set of distinct clinical predictors is useful in selecting CMV-seropositive patients at highest risk for worse outcome. A combination of clinical predictors, biomarkers, and immunologic correlates might allow
Critical Care Medicine
for improvement in stratifying highest at-risk patients for feasibility of an antiviral prophylaxis trial for clinical efficacy.
REFERENCES
1. Walton AH, Muenzer JT, Rasche D, et al: Reactivation of multiple viruses in patients with sepsis. PLoS One 2014; 9:e98819 2. Kalil AC, Florescu DF: Prevalence and mortality associated with cytomegalovirus infection in nonimmunosuppressed patients in the intensive care unit. Crit Care Med 2009; 37:2350–2358 3. Limaye AP, Kirby KA, Rubenfeld GD, et al: Cytomegalovirus reactivation in critically ill immunocompetent patients. JAMA 2008; 300:413–422 4. Heininger A, Haeberle H, Fischer I, et al: Cytomegalovirus reactivation and associated outcome of critically ill patients with severe sepsis. Crit Care 2011; 15:R77 5. Ong DSY, Klein Klouwenberg PMC, Verduyn Lunel FM, et al: Cytomegalovirus Seroprevalence as a Risk Factor for Poor Outcome in Acute Respiratory Distress Syndrome. Crit Care Med 2015; 43:394–400 6. Simanek AM, Dowd JB, Pawelec G, et al: Seropositivity to cytomegalovirus, inflammation, all-cause and cardiovascular disease-related mortality in the United States. PLoS One 2011; 6:e16103 7. Schmaltz HN, Fried LP, Xue QL, et al: Chronic cytomegalovirus infection and inflammation are associated with prevalent frailty in community-dwelling older women. J Am Geriatr Soc 2005; 53:747–754 8. Muhlestein JB, Horne BD, Carlquist JF, et al: Cytomegalovirus seropositivity and C-reactive protein have independent and combined predictive value for mortality in patients with angiographically demonstrated coronary artery disease. Circulation 2000; 102:1917–1923 9. Grahame-Clarke C, Chan NN, Andrew D, et al: Human cytomegalovirus seropositivity is associated with impaired vascular function. Circulation 2003; 108:678–683 10. Barnes LL, Capuano AW, Aiello AE, et al: Cytomegalovirus infection and risk of Alzheimer disease in older black and white individuals. J Infect Dis 2014 Aug 8. [Epub ahead of print] 11. Lichtner M, Cicconi P, Vita S, et al: Cytomegalovirus coinfection is associated with an increased risk of severe non-AIDS-defining events in a large cohort of HIV-infected patients. J Infect Dis 2014 Jul 31. [Epub ahead of print] 12. Hunt PW, Martin JN, Sinclair E, et al: Valganciclovir reduces T cell activation in HIV-infected individuals with incomplete CD4+ T cell recovery on antiretroviral therapy. J Infect Dis 2011; 203:1474–1483 13. Chilet M, Aguilar G, Benet I, et al: Virological and immunological features of active cytomegalovirus infection in nonimmunosuppressed patients in a surgical and trauma intensive care unit. J Med Virol 2010; 82:1384–1391 14. Chiche L, Forel JM, Roch A, et al: Active cytomegalovirus infection is common in mechanically ventilated medical intensive care unit patients. Crit Care Med 2009; 37:1850–1857 15. Reddehase MJ, Podlech J, Grzimek NK: Mouse models of cytomegalovirus latency: Overview. J Clin Virol 2002; 25(Suppl 2):S23–S36 16. De Vlieger G, Meersseman W, Lagrou K, et al: Cytomegalovirus serostatus and outcome in nonimmunocompromised critically ill patients. Crit Care Med 2012; 40:36–42
www.ccmjournal.org
499
Copyright of Critical Care Medicine is the property of Lippincott Williams & Wilkins and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
