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Bhide M, Singh O, Nasa P, Juneja D. Cytomegalovirus infection in non-immunocompromised critically ill patients: A management perspective. World J Virol 2024; 13:89135. [PMID: 38616856 PMCID: PMC11008403 DOI: 10.5501/wjv.v13.i1.89135] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/21/2023] [Revised: 12/18/2023] [Accepted: 12/26/2023] [Indexed: 03/11/2024] Open
Abstract
Critically ill patients are a vulnerable group at high risk of developing secondary infections. High disease severity, prolonged intensive care unit (ICU) stay, sepsis, and multiple drugs with immunosuppressive activity make these patients prone to immuneparesis and increase the risk of various opportunistic infections, including cytomegalovirus (CMV). CMV seroconversion has been reported in up to 33% of ICU patients, but its impact on patient outcomes remains a matter of debate. Even though there are guidelines regarding the management of CMV infection in immunosuppressive patients with human immunodeficiency virus/ acquired immuno deficiency syndrome, the need for treatment and therapeutic approaches in immunocompetent critically ill patients is still ambiguous. Even the diagnosis of CMV infection may be challenging in such patients due to non-specific symptoms and multiorgan involvement. Hence, a better understanding of the symptomatology, diagnostics, and treatment options may aid intensive care physicians in ensuring accurate diagnoses and instituting therapeutic interventions.
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Affiliation(s)
- Madhura Bhide
- Institute of Critical Care Medicine, Max Super Speciality Hospital, Saket, New Delhi 110017, India
| | - Omender Singh
- Institute of Critical Care Medicine, Max Super Speciality Hospital, Saket, New Delhi 110017, India
| | - Prashant Nasa
- Department of Critical Care Medicine, NMC Specialty Hospital, Dubai 7832, United Arab Emirates
| | - Deven Juneja
- Institute of Critical Care Medicine, Max Super Speciality Hospital, Saket, New Delhi 110017, India
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2
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Godsell J, Chan S, Slade C, Bryant V, Douglass JA, Sasadeusz J, Yong MK. Cytomegalovirus in primary immunodeficiency. Curr Opin Infect Dis 2021; 34:663-671. [PMID: 34608876 DOI: 10.1097/qco.0000000000000797] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
PURPOSE OF REVIEW Cytomegalovirus (CMV) infection and disease are well described in the setting of secondary immunodeficiency. Less is known about CMV in the context of primary immunodeficiencies (PIDs), where inborn errors in one or more arms of the immune system result in variable degrees of CMV susceptibility. RECENT FINDINGS PID presents unique challenges in the diagnosis and management of CMV disease. The clinical presentation of CMV in PID is often severe, accelerated by underlying immune dysregulation and iatrogenic immunosuppression. Here we describe the clinical significance of CMV infection in PID, the key components of immune defence against CMV and how these are affected in specific PIDs. CMV disease is under-recognized as a complication of common variable immunodeficiency (CVID). High rates of CMV end-organ disease, mortality, development of CMV resistance and prolonged antiviral use have been observed in individuals with CVID. SUMMARY We recommend that clinicians tailor their approach to the individual based on their underlying immune deficit and maintain a high index of suspicion and low threshold for treatment. More research is required to improve stratification of CMV risk in PID, develop new diagnostic tools and manage end-organ disease in this cohort.
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Affiliation(s)
- Jack Godsell
- Department of Clinical Immunology & Allergy, Royal Melbourne Hospital
| | - Samantha Chan
- Department of Clinical Immunology & Allergy, Royal Melbourne Hospital
- Immunology Division, Walter & Eliza Hall Institute of Medical Research
- Department of Medicine, University of Melbourne
| | - Charlotte Slade
- Department of Clinical Immunology & Allergy, Royal Melbourne Hospital
- Immunology Division, Walter & Eliza Hall Institute of Medical Research
| | - Vanessa Bryant
- Department of Clinical Immunology & Allergy, Royal Melbourne Hospital
- Immunology Division, Walter & Eliza Hall Institute of Medical Research
| | - Jo Anne Douglass
- Department of Clinical Immunology & Allergy, Royal Melbourne Hospital
- Department of Medicine, University of Melbourne
| | - Joe Sasadeusz
- Victorian Infectious Diseases Service, Royal Melbourne Hospital, Melbourne
| | - Michelle K Yong
- Victorian Infectious Diseases Service, Royal Melbourne Hospital, Melbourne
- Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville
- National Centre for Infections in Cancer, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
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3
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Marandu T, Dombek M, Cook CH. Impact of cytomegalovirus load on host response to sepsis. Med Microbiol Immunol 2019; 208:295-303. [DOI: 10.1007/s00430-019-00603-y] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2019] [Accepted: 03/22/2019] [Indexed: 12/24/2022]
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Li X, Huang Y, Xu Z, Zhang R, Liu X, Li Y, Mao P. Cytomegalovirus infection and outcome in immunocompetent patients in the intensive care unit: a systematic review and meta-analysis. BMC Infect Dis 2018; 18:289. [PMID: 29954328 PMCID: PMC6027797 DOI: 10.1186/s12879-018-3195-5] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2016] [Accepted: 06/18/2018] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND Cytomegalovirus (CMV) infection is common in immunocompetent patients in intensive care units (ICUs). However, whether CMV infection or CMV reactivation contributes to mortality of immunocompetent patients remains unclear. METHODS A literature search was conducted for relevant studies published before May 30, 2016. Studies reporting on CMV infection in immunocompetent patients in ICUs and containing 2 × 2 tables on CMV results and all-cause mortality were included. RESULTS Eighteen studies involving 2398 immunocompetent patients admitted to ICUs were included in the meta-analysis. The overall rate of CMV infection was 27% (95%CI 22-34%, I2 = 89%, n = 2398) and the CMV reactivation was 31% (95%CI 24-39%, I2 = 74%, n = 666). 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. When analysis was limited to detection in blood, CMV infection without antiviral drug treatment or reactivation was not significantly associated with higher mortality (OR: 1.69, 95%CI 0.81-3.54, I2 = 52%, n = 722; OR: 1.49, I2 = 63%, n = 469). CONCLUSION Critically ill patients without immunosuppression admitted to ICUs show a high rate of CMV infection. CMV infection during the natural unaltered course or reactivation in critically ill patients is associated with increased mortality, but have no effect on mortality when CMV in blood. More studies are needed to clarify the impact of CMV infection on clinical outcomes in those patients.
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Affiliation(s)
- Xi Li
- State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Disease, the First Affiliated Hospital of Guangzhou Medical University (Guangzhou Medical University), Guangzhou, China.,Intensive Care Unit, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Yongbo Huang
- State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Disease, the First Affiliated Hospital of Guangzhou Medical University (Guangzhou Medical University), Guangzhou, China.,Intensive Care Unit, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Zhiheng Xu
- State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Disease, the First Affiliated Hospital of Guangzhou Medical University (Guangzhou Medical University), Guangzhou, China.,Intensive Care Unit, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Rong Zhang
- State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Disease, the First Affiliated Hospital of Guangzhou Medical University (Guangzhou Medical University), Guangzhou, China.,Intensive Care Unit, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Xiaoqing Liu
- State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Disease, the First Affiliated Hospital of Guangzhou Medical University (Guangzhou Medical University), Guangzhou, China.,Intensive Care Unit, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Yimin Li
- State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Disease, the First Affiliated Hospital of Guangzhou Medical University (Guangzhou Medical University), Guangzhou, China. .,Intensive Care Unit, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China.
| | - Pu Mao
- State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Disease, the First Affiliated Hospital of Guangzhou Medical University (Guangzhou Medical University), Guangzhou, China. .,Department of Infection Control, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China.
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Cowley NJ, Owen A, Shiels SC, Millar J, Woolley R, Ives N, Osman H, Moss P, Bion JF. Safety and Efficacy of Antiviral Therapy for Prevention of Cytomegalovirus Reactivation in Immunocompetent Critically Ill Patients: A Randomized Clinical Trial. JAMA Intern Med 2017; 177:774-783. [PMID: 28437539 PMCID: PMC5818821 DOI: 10.1001/jamainternmed.2017.0895] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
IMPORTANCE Latent cytomegalovirus (CMV) infection is present in more than half the adult population, and a viral reactivation (ie, when the virus becomes measurable in body fluids such as blood) can occur in up to one-third of these individuals during episodes of critical illness. OBJECTIVE To determine whether antiviral therapy is safe and effective for preventing CMV reactivation in a general population of critically ill patients. DESIGN, SETTING, AND PARTICIPANTS A single-center, open-label, randomized, controlled clinical trial recruited 124 CMV-seropositive patients undergoing mechanical ventilation for at least 24 hours in the intensive care unit between January 1, 2012, and January 31, 2014. The mean baseline Acute Physiology and Chronic Health Evaluation II score of all patients was 17.6. INTERVENTIONS Patients were randomized to receive anti-CMV prophylaxis with valacyclovir hydrochloride (n = 34) or low-dose valganciclovir hydrochloride (n = 46) for up to 28 days to suppress viral reactivation, or to a control group with no intervention (n = 44). MAIN OUTCOMES AND MEASURES Time to first CMV reactivation in blood within the 28-day follow-up period following initiation of the study drug. RESULTS Among the 124 patients in the study (46 women and 78 men; mean [SD] age, 56.9 [16.9] years), viral reactivation in the blood occurred in 12 patients in the control group, compared with 1 patient in the valganciclovir group and 2 patients in the valacyclovir group (combined treatment groups vs control: hazard ratio, 0.14; 95% CI 0.04-0.50). Although this trial was not powered to assess clinical end points, the valacyclovir arm was halted prematurely because of higher mortality; 14 of 34 patients (41.2%) had died by 28 days, compared with 5 of 37 (13.5%) patients in the control arm at the point of the decision to halt this arm. Other safety end points showed similar outcomes between groups. CONCLUSIONS AND RELEVANCE Antiviral prophylaxis with valacyclovir or low-dose valganciclovir suppresses CMV reactivation in patients with critical illness. However, given the higher mortality, a large-scale trial would be needed to determine the clinical efficacy and safety of CMV suppression. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01503918.
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Affiliation(s)
- Nicholas J Cowley
- Institute of Clinical Sciences, University of Birmingham, Birmingham, England2Department of Anaesthesia and Intensive Care, Worcester Royal Hospital, Worcestershire Acute National Health Service Trust, Worcester, England
| | - Andrew Owen
- Institute of Clinical Sciences, University of Birmingham, Birmingham, England3University Hospitals Birmingham National Health Service Foundation Trust, Birmingham, England
| | - Sarah C Shiels
- University Hospitals Birmingham National Health Service Foundation Trust, Birmingham, England
| | - Joanne Millar
- University Hospitals Birmingham National Health Service Foundation Trust, Birmingham, England
| | - Rebecca Woolley
- Birmingham Clinical Trials Unit, University of Birmingham, Birmingham, England
| | - Natalie Ives
- Birmingham Clinical Trials Unit, University of Birmingham, Birmingham, England
| | - Husam Osman
- University Hospitals Birmingham National Health Service Foundation Trust, Birmingham, England
| | - Paul Moss
- University Hospitals Birmingham National Health Service Foundation Trust, Birmingham, England5Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, England
| | - Julian F Bion
- Institute of Clinical Sciences, University of Birmingham, Birmingham, England3University Hospitals Birmingham National Health Service Foundation Trust, Birmingham, England
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Al-Omari A, Aljamaan F, Alhazzani W, Salih S, Arabi Y. Cytomegalovirus infection in immunocompetent critically ill adults: literature review. Ann Intensive Care 2016; 6:110. [PMID: 27813024 PMCID: PMC5095093 DOI: 10.1186/s13613-016-0207-8] [Citation(s) in RCA: 71] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2016] [Accepted: 10/17/2016] [Indexed: 12/21/2022] Open
Abstract
Cytomegalovirus (CMV) infection is increasingly recognized in critically ill immunocompetent patients. Some studies have demonstrated an association between CMV disease and increased mortality rates, prolonged intensive care unit and hospital length of stay, prolonged mechanical ventilation, and nosocomial infections. However, there is a considerable controversy whether such association represents a causal relationship between CMV disease and unfavorable outcomes or just a marker of the severity of the critical illness. Detection of CMV using polymerase chain reaction and CMV antigenemia is the standard diagnostic approach. CMV may have variety of clinical manifestations reflecting the involvement of different organ systems. Treatment of CMV in critical care is challenging due to diagnostic challenge and drug toxicity, and building predictive model for CMV disease in critical care setting would be promising to identify patients at risk and starting prophylactic therapy. Our objective was to broadly review the current literature on the prevalence and incidence, clinical manifestations, potential limitations of different diagnostic modalities, prognosis, and therapeutic options of CMV disease in critically ill patients.
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Affiliation(s)
- Awad Al-Omari
- Critical Care and Infection Control Department, Dr. Sulaiman Al Habib Medical Group, Riyadh, Saudi Arabia. .,AlFaisal University, Riyadh, Saudi Arabia.
| | - Fadi Aljamaan
- Intensive Care Department, King Khalid University Hospital, King Saud University Medical City, King Saud University, Riyadh, Saudi Arabia
| | | | - Samer Salih
- Department of Internal Medicine, Dr. Sulaiman Al Habib Medical Group, Riyadh, Saudi Arabia
| | - Yaseen Arabi
- Intensive Care Department, King Abdullah International Medical Research Center, King Saud Bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia
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Osawa R, Wagener M, Singh N. Cytomegalovirus Infection in Patients with Sepsis Due to Bloodstream Infections: Lower Risk and Better Outcomes in New versus Already Hospitalised Intensive Care Unit Admissions. Anaesth Intensive Care 2016; 44:571-80. [DOI: 10.1177/0310057x1604400514] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Few studies have examined cytomegalovirus (CMV) reactivation exclusively in immunocompetent patients with sepsis due to bloodstream infections. In a cohort of CMV-seropositive critically ill otherwise non-immunosuppressed patients with sepsis due to bloodstream infection, weekly testing for CMV viraemia was performed. Outcomes were assessed at 30 days or until death/discharge from the intensive care unit (ICU). CMV viraemia developed in 20% (20/100) of the patients. Age ( P=0.044) and blood transfusions ( P=0.022) were significantly associated with CMV viraemia. 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). Patients hospitalised in the ICU for more than 48 hours prior to the onset of bloodstream infection were more likely to develop CMV viraemia ( P=0.006), have high-grade viraemia ( P=0.010), and fewer ICU-free days ( P=0.018) and ventilator-free days ( P=0.029) than those admitted within 48 hours of bloodstream infection. Thus, CMV reactivation was associated with fewer ICU- and ventilator-free days, however overall mortality was not affected. Patients already in the ICU at the onset of sepsis had higher risk of CMV reactivation and worse outcomes than new ICU-bound patients suggesting that a targeted approach for interventions for CMV could conceivably be directed towards those with a more protracted course of illness.
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Affiliation(s)
- R. Osawa
- Department of Medicine, University of Pittsburgh, Pittsburgh PA, USA
| | - M. Wagener
- Department of Medicine, University of Pittsburgh, Pittsburgh PA, USA
| | - N. Singh
- Department of Medicine, University of Pittsburgh, Pittsburgh PA, USA
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8
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Mansfield S, Dwivedi V, Byrd S, Trgovcich J, Griessl M, Gutknecht M, Cook CH. Broncholaveolar lavage to detect cytomegalovirus infection, latency, and reactivation in immune competent hosts. J Med Virol 2016; 88:1408-16. [PMID: 26762116 DOI: 10.1002/jmv.24472] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/08/2016] [Indexed: 12/24/2022]
Abstract
Roughly 1/3rd of immune competent patients will reactivate latent cytomegalovirus (CMV) during critical illness. There are no standard methods to detect reactivation, and some investigators have postulated that presence of DNA in BAL fluid is indicative of viral replication. To test this hypothesis, we used a murine model that allows inclusion of matched healthy controls which is not possible in human studies. BALB/c mice infected with Smith-murine CMV or PBS (mock) had BAL evaluated 7, 14, or 21 days after acute infections, during latency, or during bacterial sepsis. Plaque assay, PCR, and rtPCR were performed on BALs and concomitantly obtained lung tissue. BAL cellular compositions, including tetramer evaluation of CMV-specific T cells were evaluated by flow cytometry. CMV DNA were detected in BAL at all time-points during acute infection, becoming undetectable in all mice during latency, then were detected again during bacterial sepsis, peaking 3 weeks after onset. mCMV specific T-cells were most numerous in BAL after acute viral infections, decreasing to low levels during latency, then fluctuating during bacterial sepsis. Specifically, mCMV-specific T-cells contracted at sepsis onset, expanding 2-4 weeks post-sepsis, presumably in response to increased viral loads at that time point. Altogether, our results support the use of BAL PCR for the diagnosis of CMV replication in immune competent hosts. Additionally, we demonstrate dynamic changes in CMV-specific T cells that occur in BAL during CMV infection and during sepsis induced viral reactivation. J. Med. Virol. 88:1408-1416, 2016. © 2016 Wiley Periodicals, Inc.
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Affiliation(s)
- Sara Mansfield
- Division of Trauma, Critical Care, and Burn, Department of Surgery, Ohio State University College of Medicine, Columbus, Ohio
| | - Varun Dwivedi
- Division of Trauma, Critical Care, and Burn, Department of Surgery, Ohio State University College of Medicine, Columbus, Ohio
| | - Sara Byrd
- Division of Trauma, Critical Care, and Burn, Department of Surgery, Ohio State University College of Medicine, Columbus, Ohio
| | - Joanne Trgovcich
- Division of Trauma, Critical Care, and Burn, Department of Surgery, Ohio State University College of Medicine, Columbus, Ohio
| | - Marion Griessl
- Division of Acute Care Surgery, Trauma and Surgical Critical Care, Department of Surgery, Beth Israel Deaconess Medical Center-Harvard Medical School, Boston, Massachusetts
| | - Michael Gutknecht
- Division of Acute Care Surgery, Trauma and Surgical Critical Care, Department of Surgery, Beth Israel Deaconess Medical Center-Harvard Medical School, Boston, Massachusetts
| | - Charles H Cook
- Division of Acute Care Surgery, Trauma and Surgical Critical Care, Department of Surgery, Beth Israel Deaconess Medical Center-Harvard Medical School, Boston, Massachusetts
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10
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Papazian L, Hraiech S, Lehingue S, Roch A, Chiche L, Wiramus S, Forel JM. Cytomegalovirus reactivation in ICU patients. Intensive Care Med 2015; 42:28-37. [PMID: 26424680 PMCID: PMC7095171 DOI: 10.1007/s00134-015-4066-9] [Citation(s) in RCA: 75] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2015] [Accepted: 09/09/2015] [Indexed: 11/23/2022]
Abstract
Introduction Approximately 20 years have passed since we reported our results of histologically proven cytomegalovirus (CMV) pneumonia in non-immunocompromised ICU patients. Even if there are more recent reports suggesting that CMV may worsen the outcomes for ICU patients, there is no definite answer to this question: is CMV a potential pathogen for ICU patients or is it simply a bystander? Methods We will describe the pathophysiology of active CMV infection and the most recent insights concerning the epidemiological aspects of these reactivations. Major findings Cytomegalovirus can be pathogenic by a direct organ insult (such as for the lung), by decreasing host defences against other microorganisms and/or by enhancing the body’s inflammatory response (as in acute respiratory distress syndrome). The incidence of active CMV infection is dependent on the diagnostic method used. Using the most sophisticated available biological tools, the incidence can reach 15–20 % of ICU patients (20–40 % in ICU patients with positive CMV serology). In adequately powered cohorts of patients, active CMV infection appears to be associated with worse outcomes for mechanically ventilated ICU patients. Discussion There is no absolute direct proof of a negative impact of active CMV infection on the health outcomes of mechanically ventilated patients. Prospective randomized trials are lacking. Future trials should examine the potential benefits for health outcomes of using antiviral treatments. Such treatments could be prophylactic, pre-emptive or used only when there is an end-organ disease. Conclusion Cytomegalovirus infection may affect health outcomes for ICU patients. Additional prospective trials are necessary to confirm this hypothesis.
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Affiliation(s)
- Laurent Papazian
- Faculté de Médecine, Aix-Marseille Université, URMITE UMR CNRS 7278, 13005, Marseille, France. .,Réanimation des Détresses Respiratoires et des Infections Sévères, Assistance Publique-Hôpitaux de Marseille, Hôpital Nord, Chemin des Bourrely, 13015, Marseille, France.
| | - Sami Hraiech
- Faculté de Médecine, Aix-Marseille Université, URMITE UMR CNRS 7278, 13005, Marseille, France.,Réanimation des Détresses Respiratoires et des Infections Sévères, Assistance Publique-Hôpitaux de Marseille, Hôpital Nord, Chemin des Bourrely, 13015, Marseille, France
| | - Samuel Lehingue
- Faculté de Médecine, Aix-Marseille Université, URMITE UMR CNRS 7278, 13005, Marseille, France.,Réanimation des Détresses Respiratoires et des Infections Sévères, Assistance Publique-Hôpitaux de Marseille, Hôpital Nord, Chemin des Bourrely, 13015, Marseille, France
| | - Antoine Roch
- Faculté de Médecine, Aix-Marseille Université, URMITE UMR CNRS 7278, 13005, Marseille, France.,Service d'accueil des Urgences, Assistance Publique-Hôpitaux de Marseille, Nord, 13015, Marseille, France
| | - Laurent Chiche
- Département de Médecine Interne, Hôpital Européen, 13003, Marseille, France
| | - Sandrine Wiramus
- Service d'Anesthésie-Réanimation, Assistance Publique-Hôpitaux de Marseille, Hôpital de la Conception, 13005, Marseille, France
| | - Jean-Marie Forel
- Faculté de Médecine, Aix-Marseille Université, URMITE UMR CNRS 7278, 13005, Marseille, France.,Réanimation des Détresses Respiratoires et des Infections Sévères, Assistance Publique-Hôpitaux de Marseille, Hôpital Nord, Chemin des Bourrely, 13015, Marseille, France
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Lopez Roa P, Perez-Granda MJ, Munoz P, Catalan P, Alonso R, Sanchez-Perez E, Novoa E, Bouza E. A Prospective Monitoring Study of Cytomegalovirus Infection in Non-Immunosuppressed Critical Heart Surgery Patients. PLoS One 2015; 10:e0129447. [PMID: 26070136 PMCID: PMC4466502 DOI: 10.1371/journal.pone.0129447] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2015] [Accepted: 05/09/2015] [Indexed: 01/22/2023] Open
Abstract
Background Reactivation of cytomegalovirus (CMV) has been reported occasionally in immnunocompetent patients in the intensive care unit (ICU). The epidemiology and association of CMV infection with adverse outcome is not well defined in this population. Patients undergoing major heart surgery (MHS) are at a particularly high risk of infection. CMV infection has not been systematically monitored in MSH-ICU patients. Methods We assessed CMV plasma viremia weekly using a quantitative polymerase chain reaction assay in a prospective cohort of immunocompetent adults admitted to the MHS-ICU for at least 72 hours between October 2012 and May 2013. Risk factors for CMV infection and its potential association with continued hospitalization or death by day 30 (composited endpoint) were assessed using univariate and multivariate logistic regression analyses. Results CMV viremia at any level was recorded in 16.5% of patients at a median of 17 days (range, 3-54 days) after admission to the MHS-ICU. Diabetes (adjusted OR, 5.6; 95% CI, 1.8-17.4; p=0.003) and transfusion requirement (>10 units) (adjusted OR, 13.7; 95% CI, 3.9-47.8; p<0.001) were independent risk factors associated with CMV reactivation. Reactivation of CMV at any level was independently associated with the composite endpoint (adjusted OR, 12.1; 95% CI, 2.3-64; p=0.003). Conclusion Reactivation of CMV is relatively frequent in immunocompetent patients undergoing MHS and is associated with prolonged hospitalization or death.
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Affiliation(s)
- Paula Lopez Roa
- Department of Clinical Microbiology and Infectious Diseases, Hospital General Universitario Gregorio Marañón, Madrid, Spain
- Instituto de Investigación Biomédica Gregorio Marañón, Madrid, Spain
- * E-mail:
| | - Maria Jesus Perez-Granda
- Instituto de Investigación Biomédica Gregorio Marañón, Madrid, Spain
- Medicine Department, School of Medicine, Universidad Complutense, Madrid, Spain
- Department of Anesthesiology, Hospital General Universitario Gregorio Marañón, Madrid, Spain
| | - Patricia Munoz
- Department of Clinical Microbiology and Infectious Diseases, Hospital General Universitario Gregorio Marañón, Madrid, Spain
- Instituto de Investigación Biomédica Gregorio Marañón, Madrid, Spain
- Medicine Department, School of Medicine, Universidad Complutense, Madrid, Spain
| | - Pilar Catalan
- Department of Clinical Microbiology and Infectious Diseases, Hospital General Universitario Gregorio Marañón, Madrid, Spain
| | - Roberto Alonso
- Department of Clinical Microbiology and Infectious Diseases, Hospital General Universitario Gregorio Marañón, Madrid, Spain
- Instituto de Investigación Biomédica Gregorio Marañón, Madrid, Spain
| | - Eduardo Sanchez-Perez
- Department of Anesthesiology, Hospital General Universitario Gregorio Marañón, Madrid, Spain
| | - Emma Novoa
- Department of Anesthesiology, Hospital General Universitario Gregorio Marañón, Madrid, Spain
| | - Emilio Bouza
- Department of Clinical Microbiology and Infectious Diseases, Hospital General Universitario Gregorio Marañón, Madrid, Spain
- Instituto de Investigación Biomédica Gregorio Marañón, Madrid, Spain
- Medicine Department, School of Medicine, Universidad Complutense, Madrid, Spain
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Mansfield S, Grießl M, Gutknecht M, Cook CH. Sepsis and cytomegalovirus: foes or conspirators? Med Microbiol Immunol 2015; 204:431-7. [PMID: 25788396 PMCID: PMC4928686 DOI: 10.1007/s00430-015-0407-0] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2015] [Accepted: 03/09/2015] [Indexed: 12/21/2022]
Abstract
Cytomegalovirus (CMV) reactivation in non-immune-suppressed critically ill patients is an area of increasing interest. CMV has long been appreciated as a pathogen in immunocompromised hosts. CMV reactivates in approximately one-third of latently infected non-immune-suppressed hosts during critical illness; however, its role as a pathogen in these patients remains unclear. CMV reactivation has been linked to bacterial sepsis and likely results from inflammation, transient immune compromise, and viral epigenetic changes. While CMV may improve immune response to some bacterial infections, other data suggest that CMV induces exaggerated responses to severe infections that may be harmful to latently infected hosts. These results also suggest that previous infection history may explain significant differences seen between human septic responses and murine models of sepsis. While critically ill human hosts clearly have worse outcomes associated with CMV reactivation, determining causality remains an area of investigation, with randomized control trials currently being performed. Here we review the current literature and highlight areas for future investigation.
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Affiliation(s)
- Sara Mansfield
- Department of Surgery, The Ohio State University Medical Center, Columbus, OH, 43210, USA
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Virus nosocomiaux : mythe ou réalité ? MEDECINE INTENSIVE REANIMATION 2015. [DOI: 10.1007/s13546-014-1010-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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The impact of cytomegalovirus infection on mechanically ventilated patients in the respiratory and geriatric intensive care units. EGYPTIAN JOURNAL OF CHEST DISEASES AND TUBERCULOSIS 2014. [DOI: 10.1016/j.ejcdt.2013.09.022] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022] Open
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Coisel Y, Bousbia S, Forel JM, Hraiech S, Lascola B, Roch A, Zandotti C, Million M, Jaber S, Raoult D, Papazian L. Cytomegalovirus and herpes simplex virus effect on the prognosis of mechanically ventilated patients suspected to have ventilator-associated pneumonia. PLoS One 2012; 7:e51340. [PMID: 23236477 PMCID: PMC3517464 DOI: 10.1371/journal.pone.0051340] [Citation(s) in RCA: 78] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2012] [Accepted: 11/07/2012] [Indexed: 12/14/2022] Open
Abstract
OBJECTIVE Cytomegalovirus (CMV) and herpes simplex virus (HSV) are common viruses that can affect critically ill patients who are not immunocompromised. The aim of this study was to determine whether the identification of CMV and/or HSV in mechanically ventilated critically ill patients suspected of having pneumonia was associated with an increased mortality. DESIGN Prospective epidemiological study. SETTING Medical intensive care unit of a tertiary medical center. PATIENTS Ninety-three patients with suspected pneumonia. INTERVENTIONS Patients with suspected pneumonia had bronchoalveolar lavage and blood samples taken to confirm the diagnosis. Antigenemia was used to detect CMV in the blood. Bronchoalveolar lavage samples were submitted to testing using quantitative real-time Polymerase Chain Reaction. MEASUREMENTS AND MAIN RESULTS 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. CONCLUSIONS In critically ill patients, a CMV infection is associated with an increased mortality. Further interventional studies are needed to evaluate whether treatment could improve the prognosis.
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Affiliation(s)
- Yannael Coisel
- Service d'Anesthésie-Réanimation Saint Eloi, Centre Hospitalier Universitaire, and INSERM Unité 1046, Université Montpellier 1, Montpellier, France.
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Cook CH, Trgovcich J. Cytomegalovirus reactivation in critically ill immunocompetent hosts: a decade of progress and remaining challenges. Antiviral Res 2011; 90:151-9. [PMID: 21439328 PMCID: PMC3129598 DOI: 10.1016/j.antiviral.2011.03.179] [Citation(s) in RCA: 51] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2011] [Revised: 03/14/2011] [Accepted: 03/15/2011] [Indexed: 01/05/2023]
Abstract
Human cytomegalovirus (HCMV) is an undisputed pathogen in humans with severe immune compromise, which has historically been thought to carry little consequence in immunocompetent hosts. During the past decade, however, accumulating data suggest that significant numbers of immunocompetent humans reactivate HCMV during critical illness, and that these reactivation episodes are associated with worsened outcomes. Because most people are infected with this ubiquitous virus by adulthood, confirming pathogenicity has now become a clinical priority. In this article, we will review the incidence and implications of reactivation, the relevant immune responses and reactivation triggers relevant to the immunocompetent host. We will summarize the progress made during the past ten years, outline the work ongoing in this field, and identify the major gaps remaining in our emerging understanding of this phenomenon.
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Affiliation(s)
- Charles H Cook
- Department of Surgery, The Ohio State University, Columbus, OH 43210, USA.
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Gilbert É, Rico P, Laflamme PJ, Albert M. Low Cytomegalovirus Viremia Prevalence in a General Intensive Care Population. Chest 2011; 139:478-479. [DOI: 10.1378/chest.10-2290] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/01/2022] Open
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Abstract
Despite broad variability in study populations, methodologies for CMV detection, and analytic methods used, multiple studies have documented frequent CMV infection in non-immunocompromised adults with critical illness due to a variety of causes. Higher rates of CMV infection in studies of seropositive patients suggest that reactivation of latent infection rather than primary infection is the main mechanism in this setting. Risk factors for CMV reactivation (other than seropositivity) have not been clearly defined and there does not appear to be a consistent association with severity of illness. Furthermore, CMV reactivation in this setting has been associated with important adverse clinical outcomes, including increased duration of mechanical ventilation, longer length of stay and all-cause mortality. There are several biologically plausible mechanisms that could link CMV reactivation with adverse outcomes, including: direct lung injury (CMV pneumonia), amplification of inflammation systemically and within the lung, or predisposition to other nosocomial infections, but clinical data in the ICU setting are limited. Further observational studies are unlikely to significantly advance our understanding of the role of CMV in critically ill patients. Given the significant impact of critical illness, limited current therapeutic options, the availability of generally well-tolerated antiviral options for CMV, and the clinical data supporting a possible pathogenic role for CMV, there is a strong rationale for a randomised controlled trial of CMV prevention as a novel means of improving the outcomes of critically ill patients.
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Affiliation(s)
- Ajit P Limaye
- Department of Laboratory Medicine, University of Washington and Program in Infectious Diseases, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
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Chilet M, Aguilar G, Benet I, Belda J, Tormo N, Carbonell JA, Clari MA, Costa E, Navarro D. Virological and immunological features of active cytomegalovirus infection in nonimmunosuppressed patients in a surgical and trauma intensive care unit. J Med Virol 2010; 82:1384-91. [PMID: 20572085 DOI: 10.1002/jmv.21825] [Citation(s) in RCA: 49] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
Cytomegalovirus (CMV) reactivation occurs frequently in critically ill patients. The natural course of CMV infection and the interaction between CMV and the adaptive immune system in this setting remain poorly defined. Fifty-three CMV-seropositive patients in a surgical and trauma intensive care unit were included in this study. The CMV DNA load in tracheal aspirates (TA) and plasma (PL) was monitored by qPCR. CMV-specific T-cell immunity was assessed by intracellular cytokine staining. Plasma TNF-alpha levels were determined by ELISA. CMV reactivation occurred in 39.7% of patients (23% had CMV DNA detected only in TA). The analysis of TA allowed an earlier diagnosis in 28% of patients. Clearance of CMV DNAemia preceded that of CMV DNA in TA in some episodes. Peak CMV DNA levels were significantly higher in TA than in PL (P = 0.02). CMV reactivation developed in the presence of CMV-specific T cells. Termination of CMV reactivation was associated with an expansion of functional CMV-specific T cells. Plasma levels of TNF-alpha did not allow for the prediction of the occurrence of CMV reactivation. CMV-specific T-cell immunity is preserved in most critically ill patients experiencing CMV reactivation. Analysis of respiratory specimens is imperative for an optimal monitoring of CMV reactivation in this setting.
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Affiliation(s)
- Marifina Chilet
- Microbiology Service, Hospital Clínico Universitario, Valencia, Spain
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Cunha BA, Chak A, Durie N. Herpes simplex virus-1 late-onset ventilator-associated pneumonia: the importance of cytopathologic diagnosis. Am J Infect Control 2010; 38:249-50. [PMID: 20347638 DOI: 10.1016/j.ajic.2009.08.013] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2009] [Accepted: 08/13/2009] [Indexed: 10/19/2022]
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Prevalence and mortality associated with cytomegalovirus infection in nonimmunosuppressed patients in the intensive care unit. Crit Care Med 2009; 37:2350-8. [PMID: 19531944 DOI: 10.1097/ccm.0b013e3181a3aa43] [Citation(s) in RCA: 151] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
INTRODUCTION Cytomegalovirus is the most common viral opportunistic infection in immunocompromised patients. However, recent studies have demonstrated active cytomegalovirus infection in nonimmunosuppressed intensive care unit patients. OBJECTIVE To define the frequency and mortality rate associated with cytomegalovirus infection in nonimmunosuppressed patients in the intensive care unit. METHODS A systematic review up to October 2008 was performed. Pooled results were analyzed by fixed- and random-effects models. Cochran Q and I2 were performed for heterogeneity. RESULTS Thirteen studies (n = 1258) were selected. The overall rate of active cytomegalovirus infection was 17% (95% confidence interval [CI], 11% to 24%; p < .0001; I2 = 86%). When the patients were screened for > or =5 intensive care unit days, the overall rate of infection increased to 21% (95% CI, 15% to 29%; p < .001). The infection rate for studies that used cytomegalovirus DNA/antigen for diagnosis was 20% (95% CI, 13% to 31%; p < .0001) and for studies that used culture was 12% (95% CI, 6% to 22%; p < .0001). The cytomegalovirus rate for patients with unknown serology was 7% (95% CI, 3% to 14%; p < .0001), whereas the rate for patients with positive serology was 31% (95% CI, 22% to 42%; p < .0001). The rate of infection was higher in patients with severe sepsis: 32% (95% CI, 22% to 45%; p < .0001). And in patients with high disease severity: 32% (95% CI, 23% to 42%; p < .0001). The overall mortality rate associated with active cytomegalovirus infection was 1.93 times (95% CI, 1.29 to 2.88; p = .001) as high as that without cytomegalovirus infection. CONCLUSIONS Active cytomegalovirus infection occurs frequently in nonimmunosuppressed patients in intensive care, especially in those with positive cytomegalovirus serology, intensive care unit stay > or =5 days, severe sepsis, and high disease severity, in whom the rate of cytomegalovirus infection is up to 36%. Mortality rate is significantly doubled with cytomegalovirus, but a cause-effect relationship cannot be established yet. A large prospective cohort study on the patient population identified by our findings is needed to define who is at the highest risk for developing active cytomegalovirus infection and to determine its effects on mortality.
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Active cytomegalovirus infection is common in mechanically ventilated medical intensive care unit patients. Crit Care Med 2009; 37:1850-7. [PMID: 19384219 DOI: 10.1097/ccm.0b013e31819ffea6] [Citation(s) in RCA: 118] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
OBJECTIVE To assess the incidence, risk factors, and outcome of active cytomegalovirus (CMV) infection in nonimmunosuppressed intensive care unit (ICU) patients. DESIGN Prospective epidemiologic study. SETTING A medical ICU in a university hospital. PATIENTS Two hundred forty-two nonimmunosuppressed ICU patients mechanically ventilated for >or=2 days. INTERVENTIONS Routine pp65 antigenemia and serology for CMV were performed at admission, and then weekly. Bronchoalveolar lavage viral cultures were done when pneumonia was suspected. MEASUREMENTS AND MAIN RESULTS Thirty-nine of the 242 ICU patients (16.1%, confidence interval 11.5% to 20.7%) developed an active CMV infection, as diagnosed by positive antigenemia (85%) and/or positive rapid viral culture in bronchoalveolar lavage (26%). Antiviral treatment was initiated in 21 (54%) patients. ICU mortality (54% vs. 37%, p = 0.082) and in-hospital mortality (59% vs. 41%, p = 0.058) were increased in patients with active CMV infection, as compared with those without active CMV infection. Active CMV infection and Simplified Acute Physiology Score II at admission were associated with ICU death on multivariate analysis. The patients with active CMV infection had longer mechanical ventilation and longer ICU stay and were significantly more prone to developing bacterial nosocomial infections (p < 0.001). Logistic regression analysis showed that prior admission to other wards (p = 0.043; odds ratio [OR], 2.49), blood transfusions (p = 0.04; OR, 3.31), enteral feeding (p = 0.005; OR, 3.00), recent corticosteroid use before ICU admission (p = 0.08; OR, 2.26), and age (p = 0.07; OR, 1.026) were associated with the occurrence of active CMV infection. CONCLUSIONS : Active CMV infection is common among previously healthy patients under mechanical ventilation in a medical ICU. Further studies are needed to evaluate the role of antiviral treatments to reduce both the incidence and the outcome impact of active CMV infection.
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Osawa R, Singh N. Cytomegalovirus infection in critically ill patients: a systematic review. CRITICAL CARE : THE OFFICIAL JOURNAL OF THE CRITICAL CARE FORUM 2009; 13:R68. [PMID: 19442306 PMCID: PMC2717427 DOI: 10.1186/cc7875] [Citation(s) in RCA: 141] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 01/28/2009] [Revised: 03/25/2009] [Accepted: 05/14/2009] [Indexed: 02/06/2023]
Abstract
INTRODUCTION The precise role of cytomegalovirus (CMV) infection in contributing to outcomes in critically ill immunocompetent patients has not been fully defined. METHODS Studies in which critically ill immunocompetent adults were monitored for CMV infection in the intensive care unit (ICU) were reviewed. RESULTS CMV infection occurs in 0 to 36% of critically ill patients, mostly between 4 and 12 days after ICU admission. Potential risk factors for CMV infection include sepsis, requirement of mechanical ventilation, and transfusions. Prolonged mechanical ventilation (21 to 39 days vs. 13 to 24 days) and duration of ICU stay (33 to 69 days vs. 22 to 48 days) correlated significantly with a higher risk of CMV infection. Mortality rates in patients with CMV infection were higher in some but not all studies. Whether CMV produces febrile syndrome or end-organ disease directly in these patients is not known. CONCLUSIONS CMV infection frequently occurs in critically ill immunocompetent patients and may be associated with poor outcomes. Further studies are warranted to identify subsets of patients who are likely to develop CMV infection and to determine the impact of antiviral agents on clinically meaningful outcomes in these patients.
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Affiliation(s)
- Ryosuke Osawa
- Infectious Diseases Section, VA Medical Center, University Drive C, Pittsburgh, PA 15420 USA.
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A silent killer: cytomegalovirus infection in the nonimmunocompromised critically ill patient. Crit Care Med 2008; 36:3261-4. [PMID: 19020435 DOI: 10.1097/ccm.0b013e31818f24c3] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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von Müller L, Klemm A, Weiss M, Schneider M, Suger-Wiedeck H, Durmus N, Hampl W, Mertens T. Active cytomegalovirus infection in patients with septic shock. Emerg Infect Dis 2007; 12:1517-22. [PMID: 17176565 PMCID: PMC3290950 DOI: 10.3201/eid1210.060411] [Citation(s) in RCA: 70] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023] Open
Abstract
Cytomegalovirus reactivation occurred in one third of patients and was associated with prolonged ventilation and stay in an intensive care unit. Cytomegalovirus (CMV) is a pathogen of emerging importance for patients with septic shock. In this prospective study, 25 immunocompetent CMV-seropositive patients with septic shock and an intensive care unit stay of >7 days were monitored by using quantitative pp65-antigenemia assay, shell vial culture, and virus isolation. Within 2 weeks, active CMV infection with low-level pp65-antigenemia (median 3 positive/5 × 105 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). The association between active CMV infection and increased illness could open new therapeutic options for patients with septic shock. Future interventional studies are required.
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Affiliation(s)
- Torsten W Wiegand
- Massachusetts Eye and Ear Infirmary, 243 Charles Street, Boston, MA 02114, USA
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Jaber S, Chanques G, Borry J, Souche B, Verdier R, Perrigault PF, Eledjam JJ. Cytomegalovirus infection in critically ill patients: associated factors and consequences. Chest 2005; 127:233-41. [PMID: 15653989 DOI: 10.1378/chest.127.1.233] [Citation(s) in RCA: 133] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023] Open
Abstract
OBJECTIVE To determine the prevalence, associated findings, and consequences of cytomegalovirus (CMV) antigenemia in critically ill patients. DESIGN A retrospective, case-control clinical study. SETTING A 12-bed university hospital medical-surgical ICU. PATIENTS Two hundred thirty-seven patients with fever for > 72 h, without proven evidence of bacteriologic and/or fungal origin, and whose pp65 antigenemia assays were studied. Patients with HIV infection and transplant recipients were excluded. INTERVENTIONS None. MEASUREMENTS AND RESULTS CMV antigenemia was diagnosed within 20 +/- 12 days (mean +/- SD) after ICU admission in 17% patients in whom the pathology was suspected. The 40 patients in the CMV group were matched with 40 other patients in the control group. 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). CONCLUSIONS CMV antigenemia is not an uncommon diagnosis in critically ill ICU patients with unexplained prolonged fever after 10 days of hospitalization, regardless of their immune system status. Although associated with a higher morbidity and mortality, the clinical significance of CMV is unknown. Further prospective studies should evaluate the impact on ICU outcome and whether CMV is truly a pathogen or simply another indicator of immunosuppression.
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Affiliation(s)
- Samir Jaber
- Intensive Care Unit and Transplantation Department, Saint Eloi Hospital, University Hospital of Montpellier, Montpellier, France.
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Viral Infections in ICU Patients. TROPICAL AND PARASITIC INFECTIONS IN THE INTENSIVE CARE UNIT 2005. [PMCID: PMC7120721 DOI: 10.1007/0-387-23380-6_4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
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Gandhi MK, Khanna R. Human cytomegalovirus: clinical aspects, immune regulation, and emerging treatments. THE LANCET. INFECTIOUS DISEASES 2004; 4:725-38. [PMID: 15567122 DOI: 10.1016/s1473-3099(04)01202-2] [Citation(s) in RCA: 394] [Impact Index Per Article: 18.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
After initial infection, human cytomegalovirus remains in a persistent state with the host. Immunity against the virus controls replication, although intermitent viral shedding can still take place in the seropositive immunocompetent person. Replication of cytomegalovirus in the absence of an effective immune response is central to the pathogenesis of disease. Therefore, complications are primarily seen in individuals whose immune system is immature, or is suppressed by drug treatment or coinfection with other pathogens. Although our increasing knowledge of the host-virus relationship has lead to the development of new pharmacological strategies for cytomegalovirus-associated infections, these strategies all have limitations-eg, drug toxicities, development of resistance, poor oral bioavailability, and low potency. Immune-based therapies to complement pharmacological strategies for the successful treatment of virus-associated complications should be prospectively investigated.
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Affiliation(s)
- Maher K Gandhi
- Tumour Immunology Laboratory at the Queensland Institute of Medical Research, Brisbane, Australia
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Abstract
Les infections virales respiratoires communautaires sont fréquentes et le plus souvent bénignes. Beaucoup d'agents différents comme les virus influenza, ou para-influenza, le virus respiratoire syncitial, les rhinovirus, coronavirus, adénovirus et les herpès virus peuvent être isolés chez les patients immunocompétents. Parmi ces virus, le cytomégalovirus (CMV) peut être responsable de pneumonie nosocomiale en réanimation. Le diagnostic des infections virales est difficile car les signes cliniques sont non spécifiques et l'isolement du virus responsable difficile. Cependant, une symptomatologie clinique associant fièvre, myalgies, céphalées, pharyngite est fréquente dans les infections à Inflenza qui peuvent aboutir à des tableaux sévères. Enfin, le virus plus récent responsable d'infection respiratoire est un virus nouvellement découvert de la famille des coronavirus, le SRAS-CoV qui a été responsable d'une épidémie d'infections respiratoires sévères. Les pneumonies virales sont fréquentes mais probablement non diagnostiquées chez les patients immunocompétents. Cependant le diagnostic est nécessaire car pour la plupart des pathogènes il existe un traitement efficace. Le diagnostic repose sur l'histologie mais de nouvelles techniques comme la PCR doivent devenir d'utilisation courante pour améliorer le rendement diagnostique.
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Cook CH, Martin LC, Yenchar JK, Lahm MC, McGuinness B, Davies EA, Ferguson RM. Occult herpes family viral infections are endemic in critically ill surgical patients. Crit Care Med 2003; 31:1923-9. [PMID: 12847384 DOI: 10.1097/01.ccm.0000070222.11325.c4] [Citation(s) in RCA: 93] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
OBJECTIVE Herpes family viruses have been recognized as pathogens for many years in immunosuppressed transplant or human immunodeficiency virus patients, but they have garnered little attention as potential pathogens in the nonimmunosuppressed critically ill. The objective of this study was to define the prevalence of and risk factors for development of herpes family virus infection in chronic critically ill surgical patients. DESIGN Prospective epidemiologic study. SETTING A 38-bed surgical intensive care unit in a major university hospital. PATIENTS Nonimmunosuppressed intensive care unit patients in intensive care unit for >/=5 days. INTERVENTIONS None; patients received no antiviral treatment during the study. MEASUREMENTS AND MAIN RESULTS 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. In contrast, herpes simplex virus-positive patients had lengths of hospital admissions, lengths of intensive care unit admissions, and periods of ventilator dependence comparable with patients without viral infections (p >.05). CONCLUSIONS There is a significant prevalence (22-49%) of occult active herpes family viruses in chronic critically ill surgical patients. The clinical significance of these viral infections is unknown, although CMV+ patients have significantly higher morbidity rates than CMV- patients. Several factors suggest pathogenicity, but further study is needed to define causality.
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Affiliation(s)
- Charles H Cook
- Department of Surgery, The Ohio State University, Columbus, USA
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Heininger A, Jahn G, Engel C, Notheisen T, Unertl K, Hamprecht K. Human cytomegalovirus infections in nonimmunosuppressed critically ill patients. Crit Care Med 2001; 29:541-7. [PMID: 11373417 DOI: 10.1097/00003246-200103000-00012] [Citation(s) in RCA: 123] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
OBJECTIVE To assess the occurrence of active human cytomegalovirus (HCMV) infection and HCMV disease and to evaluate potential risk factors in immunocompetent intensive care patients after major surgery or trauma. DESIGN A prospective clinical study. SETTING An anesthesiological intensive care unit (ICU) in a university hospital. PATIENTS Fifty-six anti-HCMV immunoglobulin G (IgG) seropositive patients without manifest immunodeficiency whose simplified acute physiology score (SAPS II) value rose to >or=41 points during their ICU stay. INTERVENTIONS Once a week, the patients were examined for active HCMV infection by polymerase chain reaction and by viral cultures from blood and lower respiratory tract secretions. Three times a week, detailed clinical examination for signs of HCMV disease was carried out. MEASUREMENTS AND MAIN RESULTS Twenty of the 56 ICU patients (35.6%) who met the study criteria of a SAPS II score >40 points and anti-HCMV IgG seropositivity developed an active HCMV infection as diagnosed by the detection of HCMV DNA in leukocytes, plasma, or respiratory tract secretions. In seven patients, the virus was isolated in the respiratory tract secretions. Severe HCMV disease appeared in two patients with pneumonia or encephalitis respectively. 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). CONCLUSIONS Even in a group of ICU patients without manifest immunodeficit who were anti-HCMV IgG seropositive and had reached a SAPS II score of >or=41 points, active HCMV infection occurred frequently (35.6%). Septic patients were affected twice as often as the total study population. In 2 of the 20 cases, active HCMV infection progressed to severe HCMV disease. Proper diagnosis demands special clinical attention combined with extended virological examinations. Further studies in a larger patient group should evaluate the influence of HCMV on ICU mortality.
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Affiliation(s)
- A Heininger
- Klinik für Anästhesiologie und Transfusionsmedizin, Institut für Anästhesiologie, Universitätsklinikum Tübingen, Germany.
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Paya CV. Prevention of cytomegalovirus disease in recipients of solid-organ transplants. Clin Infect Dis 2001; 32:596-603. [PMID: 11181123 DOI: 10.1086/318724] [Citation(s) in RCA: 94] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2000] [Revised: 10/02/2000] [Indexed: 01/18/2023] Open
Abstract
The introduction and combination of more-potent immunosuppressive regimens, and the increased transplantation of organs into more severely ill patients, have again placed cytomegalovirus (CMV) disease in the spotlight of posttransplantation complications. Both direct and associated complications related to CMV need to be considered in understanding the pathogenesis of CMV infection after solid-organ transplantation. New diagnostic methods with higher sensitivity for the detection of CMV and the ability to quantify CMV indicate that low levels of CMV replication are present in many patients who don't have clinical symptoms ascribed to CMV infection. How these low levels of CMV replication impact the outcome of the transplanted graft remains unknown. In addition, there needs to be further study regarding whether only patients at high risk for developing CMV disease or, also, those with clinically asymptomatic levels of CMV replication should be the target of effective preventive regimens. This review summarizes our current knowledge of the pathogenesis of CMV infection after solid-organ transplantation, and it outlines different effective preventive regimens and approaches.
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Affiliation(s)
- C V Paya
- Division of Infectious Diseases and Transplant Center, Mayo Clinic, Rochester, MN 55905. USA.
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Heininger A, Vogel U, Aepinus C, Hamprecht K. Disseminated fatal human cytomegalovirus disease after severe trauma. Crit Care Med 2000; 28:563-6. [PMID: 10708201 DOI: 10.1097/00003246-200002000-00046] [Citation(s) in RCA: 23] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
OBJECTIVE Disseminated human cytomegalovirus (HCMV) disease is considered to be uncommon in critically ill but otherwise not immunosuppressed patients. We describe the case of a trauma victim who developed fatal HCMV disease that initially presented as pseudomembranous colitis and resulted in sudden cardiac death. DESIGN Case report of fatal HCMV disease in a previously healthy patient after multiple trauma. SETTING Surgical intensive care unit (ICU). PATIENT A 63-yr-old male patient with multiple injuries. INTERVENTIONS AND MEASUREMENTS Under ICU treatment, symptoms of HCMV reactivation presenting as pseudomembranous colitis appeared 32 days after trauma. Detailed laboratory examinations for HCMV infection were performed, including complement fixation titer, immunoglobulin G and M, polymerase chain reaction, and virus isolation. RESULTS The intravital detection of HCMV DNA in serum, leukocytes, and a colonic biopsy specimen indicated HCMV reactivation. Postmortem examination findings, including positive viral cultures, showed severe disseminated HCMV disease with involvement of the colon and myocardium. CONCLUSIONS The lack of specific clinical symptoms of HCMV disease and the delay until viral culture results are available make an exact and timely diagnosis of HCMV disease difficult. Its prevalence in critically ill but otherwise not immunosuppressed patients is currently unknown and possibly underestimated. Because severe illness or trauma can cause immunodysfunction and, thus, may contribute to an increased rate of HCMV disease, detailed studies are warranted to evaluate the real risk in the ICU setting.
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Affiliation(s)
- A Heininger
- Klinik für Anästhesiologie, University of Tübingen, Germany
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