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Table 2 Summary of studies assessing CMV disease in ICU patients

From: Cytomegalovirus infection in immunocompetent critically ill adults: literature review

Year of publication Study Study design Patient population Patients no. Method and specimen Frequency of monitoring Incidence (%) Mortality (%)
CMV positivea CMV negativeb
1990 Domart et al. [31] Prospective, single center Mediastinitis, post-cardiac surgery
Patients in whom viral cultures could be done within 10 days of surgical debridement
115 Serology for CMV IgG
Viral culture blood and urine. Positive cases: positive CMV culture
Within first 10 days of debridement then every 3 weeks 25 55* 37*
1994 Docke et al. [50] Unidentified Septic patients 60 1—CMV culture in blood. 2—Immunocytological detection of CMV antigens in blood. 3—PCR amplification in blood. 4—TNF and interleukin six assays. Positive cases: any positive PCR or culture or antigen detection Once 97.7 NA  
1996 Stephan et al. [51] Prospective, single center Mechanically ventilated 23 Culture, PCR
Blood and BAL
Unclear 0 0  
1996 Papazian et al. [39] Retrospective
Single center
Patients with ventilator-associated pneumonia 86 Histopathology
Autopsies and open lung biopsy
Once
22.4 ± 8.8 days after admission to the intensive care unit
29 NA NA
1998 Kutza et al. [29] Prospective, single center SICU
Septic patients with positive CMV IgG serology
34 CMV IgG serology
CMV antigenemia
CMV DNA PCR in blood
Serum cytokines: TNF alpha, IL-1b, and IL-6 measured by ELISAs. Positive cases: positive CMV antigenemia and/or CMV DNA PCR in blood
1—Blood samples were collected on day 1 of sepsis, then twice weekly during ICU stay, then once weekly after release from the ICU, until recovery or death 32 73.9* 63.6*
1998 Cook et al. [27] Prospective, case–control single center Postoperative general SICU. Septic patients with no identifiable bacterial or fungal source. Positive BAL or blood or sputum CMV culture 12 CMV and HSV viral culture from BAL, blood or sputum. All cases included had positive CMV culture CMV was cultured in diploid human foreskin fibroblast culture for 6 weeks
Plasma was evaluated by shell vial technique to IE antigen at 24 h. HSV cultures
100 65α 35α
2001 Heininger et al. [24] Prospective, single center SICU
Patients with SAPS II >40 and positive serology
56 CMV DNA PCR and/or viral culture
Leukocytes, plasma, and lower respiratory tract secretions
Positive cases: positive PCR
Once weekly 35.6 55* 36.2*
2002 Razonable et al. [52] Prospective
Case–control
Single center
Mixed ICU 120 CMV and HHV-6 and HHV-7 DNA by PCR in blood
Positive cases: positive PCR
4th days after ICU admission <1 NA  
2003 Cook et al. [23] Prospective
Single center
SICU
Patients staying for 5 days or more in SICU
104 Serology in blood
CMV and HSV cultures in blood and sputum
Positive cases: positive CMV culture
Once weekly until discharge from SICU 9.6 50* 26.5*
2005 Jaber et al. [28] Retrospective, matched case–control, single center Medical, surgical, and transplant unit
Non-immune-compromised patients
237 PP65 antigen
Blood
Positive cases: positive CMV antigenemia
1—Clinical judgment. 2—The diagnosis of CMV antigenemia was defined by a positive CMV pp65 antigenemia assay result 16.8 50α 28α
2006 von Muller et al. [53] Prospective observational single center Anesthesiological intensive care unit. Non-immunocompromized CMV IgG-seropositive patients with septic shock with ICU stay for at least 7 days 23 Serology
CMV antigenemia
Blood. CMV reactive T helper 1 lymphocytes
Positive cases: positive CMV antigenemia
Twice during 1st week then weekly until discharge
Positive cases: positive antigenemia
30.4 57* 38*
2008 Ziemann et al. [2] Retrospective, single center Mixed ICU
Patients treated for at least 14 days in ICU
99 CMV DNA PCR
Blood. Positive cases: at least two positive samples
Based on the decision of the treating team 35 28.6α 10.9α
2008 Limaye et al. [1] Prospective, multicenter Mixed ICU, positive anti-CMV IgG 120 PCR
Blood
Positive cases: positive blood CMV PCR
Thrice weekly until death or discharge 33 CMV disease was significantly associated with death or continued hospitalization after 30 days  
2009 Chiche et al. [26] Prospective, single center MICU
Ventilated patients for at least 2 days
242 CMV serology and antigenemia. CMV culture on BAL if VAP suspected, antigenemia on the day of BAL. Other organ Virologic studies based on clinical suspicion. Positive cases: positive antigenemia or BAL CMV culture Within 48 h of ICU admission and once weekly until discharge 16.1 54* 37*
2010 Chilet et al. [54] Prospective observational
Single center
Anesthesiological ICU
Single center
CMV-seropositive, ICU stay longer than 5 days
53 CMV PCR
Tracheal aspirate and plasma
Plasma tumor necrosis factor alpha
Once a week 39.7 61* 46*
2010 Smith et al. [55] Prospective single center Tertiary ICU
Mechanically ventilated patients
174 Respiratory secretions CMV PCR
Thrice weekly
  19 NA  
2011 Iahangard Prospective ICU
CMV-seropositive patients
132 CMV IgG serology
PCR in blood
Weekly 34 The overall mortality rate associated with active CMV infection was 1.93 times higher than that without CMV infection  
2011 Bordes et al. [56] Prospective
Single center
Severe burn unit
Burn surface area more than 15%
29 CMV DNA
Blood
First sample on admission then one to twice weekly until discharge 55 33* 20*
2011 Uegaki Retrospective
Single center
ICU 67 CMV antigenemia After 7 days of admission if intensivists suspected CMV 52 NA  
2011 Heininger et al. [38] Prospective, observational, single center Severe sepsis, positive anti-CMV IgG 86 Viral culture from tracheal secretions. Qualitative CMV DNA PCR from leukocytes, plasma, tracheal secretions
Quantitative CMV DNA PCR from positive plasma and tracheal secretions
HSV DNA PCR from tracheal secretions
Positive cases: positive PCR from any source
Once weekly until discharge from hospital or death 40.7 37.1* 35.3*
2012 De Vlieger et al. [57] Prospective, MICU and SICU, single center
(Van Den Berge study)
Admitted for at least 3 days in ICU
Mechanically ventilated in SICU
MICU regardless of mechanical ventilation
1504 CMV IgG serology Within first 2 days of admission 64 19.2* 17.1*
2012 Chiche et al. [10] Prospective
Single center
MICU
CMV-seropositive patients
82 CMV serology
CMV antigenemia
Lymphocyte subset
Interferon-γ
Within 48 h of admission then once weekly until discharge 27 40* 13.3*
2012 Coisel et al. [37] Prospective single center MICU
Mechanically ventilated suspected of having pneumonia
10% were previously immunocompromized
93 1—Serology (IgM and IgG) for cytomegalovirus (CMV) and herpes simplex (HSV) using (ELISA)
Blood PCR was not routinely done
2—CMV antigen detection in blood
3—CMV and HSV DNA PCR on BAL
Positive cases: positive CMV PCR in BAL or positive antigenemia or positive IgM
Within 12 h of pneumonia diagnosis 24 55α 20α
2013 Clari et al. [9] Prospective single center SICU
Mechanically ventilated patients
CMV seropositive
31 CMV serology at baseline
CMV-specific interferon-γ-producing CD8, CD4 T lymphocytes
CMV PCR in blood and tracheal aspirate
2–8 samples per patient were analyzed for T lymphocytes subset and CMV PCR 54.8 47* 35*
2014 Ishioka et al. [58] Prospective
Single center
Cardiac ICU
Post-surgery
100 CMV PP65 antigenemia
Serum
On admission, day 7 and day 14 4 0* 1*
2014 Osman Prospective
Single center
Respiratory and geriatric ICU 51 CMV PCR
Blood
NA 68.6 74.3α 31.3α
2014 Walton et al. [59] Prospective
Single center
MICU and SICU
Critically ill septic and non-septic patients versus healthy volunteers
560 CMV IgG
CMV PCR
Blood
Daily
Starting within 24–72 h of admission
24.2 Significant increase in 90 days mortality in CMV-positive patients compared to CMV-negative ones  
2015 Ong et al. [40] Multicenter prospective cohort Mixed ICU (tertiary care referral centers)
ARDS patients on mechanical ventilation for at least 4 days
271 CMV IgG if positive CMV PCR in blood Weekly for maximum 30 days 27 46α 28α
2015 Frantzeskaki et al. [12] Prospective, observational two centers Mixed ICU, mechanically ventilated, seropositive anti-CMV IgG 80 CMV DNA PCR
Blood
At admission, then weekly until day 28 or discharge from ICU or death 13.75 18* 22*
2015 Ong et al. [60] Multicenter prospective cohort Mixed ICU (tertiary care referral centers)
ARDS patients on mechanical ventilation for at least 4 days
209 CMV IgG between days 5 and 14 of admission
If positive CMV DNA PCR in plasma
CMV DNA PCR on day 14 or ICU discharge date (whichever first) then weekly 26 28* 16*
  1. Positive serology: positive anti-CMV IgG or IgM
  2. ELISA enzyme-linked immunosorbent assay, PCR polymerase chain reaction, CMV cytomegalovirus, ARDS acute respiratory distress syndrome, BAL bronchoalveolar lavage, MICU medical intensive care unit, SICU surgical intensive care unit, SAPS simplified acute physiology score, ICU intensive care unit, ELISA enzyme-linked immunosorbent assay
  3. aCMV positive based on study methodology
  4. bCMV negative based on study methodology
  5. * Nonsignificant difference in mortality
  6. αStatistically significant difference in mortality between groups
  7. δ24% in seropositive without reactivation
  8. Considered infected if at least two positive results