Cytomegalovirus infection in non-immunocompromised critically ill patients: A management perspective

Table 1 Risk factors for cytomegalovirus reactivation

Risk factors for CMV reactivation	Ref.	Statistics
High disease severity	Kalil et al[1]	High disease severity (APACHE > 20, SAPS > 40 or SOFA > 10) 32% vs low disease severity (APACHE < 20, SAPS < 40 or SOFA < 10) 13% (P < 0.0001)
	Ong et al[10]	Mean APACHE IV 91 (71-113) vs 76 (62-99) (P < 0.01)
Prolonged ICU stay	Kalil et al[1]	1% < 5 d vs 21% at > 5 d (P < 0.001)
	von Müller et al[11]	32% by day 14
	Limaye et al[2]	33% by day 12
Sepsis, septic shock	Kalil et al[1]	Reactivation of CMV in patients with and without septic shock: 32% vs 15% (P < 0.0001)
	Osawa et al[12]	OR 4.62 (P = 0.02)
	Ong et al[10]	Reactivation of CMV in patients with and without septic shock 57% vs 41% (P = 0.02)
Previous seropositivity	Kalil et al[1]	Reactivation of CMV in patients with and without previous seropositivity for CMV: 31% vs 7% (P < 0.0001)
Mechanical ventilation	Osawa et al[12]	OR: 8.5 (95%CI 1.1 to 66.5 for high-grade CMV viremia, i.e. CMV PCR > 1000 copies/mL)
	Limaye et al[2]	OR 2.5 (0.9-7.3) (P = 0.09)
Multiple blood transfusions	Frantzeskaki et al[9]	OR 1.50 (P = 0.02)
	Chiche et al[13]	OR 3.31 (P = 0.04)
	Limaye et al[2]	OR 9.1 (1.0-84.7) (P = 0.05)
Surgical patients	Kalil et al[1]	Rate of CMV reactivation in medical ICUs: 8% vs surgical ICUs: 23% (P < 0.001)
Steroid use	Jaber et al[14]	CMV reactivation in patients with and without steroid use: 55% vs 33% (P = 0.04)
	Chiche et al[13]	OR 2.26 (P = 0.08)
Renal failure	Jaber et al[14]	58% vs 33% (P = 0.02)
	Ong et al[10]	16% vs 6% (P < 0.01)
Male	Limaye et al[2]	OR 3.6 (P = 0.005)
Raised CRP	Frantzeskaki et al[9]	OR 1.01 (P = 0.02)

CMV: Cytomegalovirus; APACHE: Acute physiology and chronic health evaluation; SAPS: Simplified acute physiology score; SOFA: Sequential organ failure assessment; ICU: Intensive care unit; OR: Odd’s ratio, PCR: Polymerase chain reaction; CRP: C-reactive protein.

Table 2 Patient outcomes in studies in critically ill immunocompetent patients

Year of publication	Ref.	Study design	Patient population	Sample size	Prevalence of CMV (%)	Mortality rate (%) CMV positive vs negative	ICU stay	Ventilator duration	Other outcomes
1990	Domart et al[22]	Prospective, single center	Mediastinitis following cardiac surgery	115	25	55 vs 37 (P < 0.01)	69+/-36 vs 48+/-27 (P < 0.05)	ND
1996	Stéphan et al[16]	Prospectivecase series, single center	Medico-surgical patients on mechanical ventilation	23	ND	52	ND	ND
1996	Papazian et al[15]	Prospective single centre	Ventilator associated pneumonia	86	29	ND	ND	No difference (P > 0.05)	Severe hypoxemia CMV +/- (72 vs 95 mmHg, P < 0.05)
1998	Kutza et al[7]	Prospective longitudinal, singles centre	Septic shock	34	32.4	ND	ND	ND	CMV active had higher TNFα, IL1ß, ALT
2006	Cook et al[23]	Prospective, singles centre	SICU	20		65 vs 33 (P = 0.006)	83.5 vs 36 (P < 0.03)	ND	92 vs 25 (P < 0.004)
2011	Heininger et al[24]	Prospective, singles center	Medical ICU with SAPS II > 40	56		55 vs 36	30 vs 23 (P = 0.0375)	ND
2005	Jaber et al[14]	Retrospective matched case control study, single centre	Medico-surgical ICU patients	80		20 vs 11 (P = 0.02)	41 vs 31 (P = 0.04)	35 vs 24 (P = 0.03)	Bacteremia 15 vs 7 (P = 0.05)
2006	von Müller et al[11]	Prospective observational study, single centre	Septic shock	38	18.4	57 vs 38 (NS)	54 vs 19 (P = 0.0025)	42 vs 16 (P = 0.0025)
2008	Ziemann et al[25]	Retrospective study	Medical ICU	138	35	28.6 vs 10.9 (P = 0.048)	32.6 vs 22.1 (P < 0.001)
2008	Limaye et al[2]	Prospective, multicentre	Mixed ICU	120	33	ND
2009	Chiche et al[13]	Prospective study	Medical ICU on mechanical ventilator for > 2 d	242	16.1	54 vs 37 (P = 0.082)	32 vs 12 (P < 0.001)	27 vs 10 (P < 0.001)	Ventilator free days at 28 and 60, P < 0.001. Increased risk of bacteremia, P < 0.033, increased bacterial nosocomial pneumonia, P < 0.001
2010	Chilet et al[26]	Prospective observational, single center	Surgical and trauma ICU	53	39.7	61 vs 46 (P = 0.40)	37 vs 11 (P = 0.01)	ND	TNF alpha, P = 0.80. CMV specific T cell response CD8+, P = 0.05. CD4, P = 0.04
2011	Heininger et al[24]	Prospective observational study	Mixed ICU	86	40.6	37.1 vs 35.3, (P = 0.861)	30 vs 12 (P < 0.001)	22 vs 7.5 (P = 0.003)
2009	Chiche et al[13]	Prospective, observation	Medical ICU	51	18	40 vs 13.3 (P = 0.21)	28 vs 14 (P = 0.013)	24 vs 8 (P = 0.019)	Bacterial VAP 40 vs 26.6 (P = 0.70)
2012	Coisel et al[27]	Prospective study	Medical ICU	93	ND	55 vs 20 (P < 0.01)	25.5 vs 13 (P = 0.037)	Bacteremia (%) 19.5 vs 10 (P = 0.009)	VFD at 60 (d) median [IQR] 0 [0-25] vs 50 [11.5-58] (P = 0.001). Shock (%) 77 vs 30 (P = 0.001, acute renal failure (%) 50 vs 16 (P = 0.01)
2013	Clari et al[28]	Prospective observational, single center study	Surgical and trauma ICU	48	0.27	8 out of 17 (reactivation of CMV) vs 5 out of 14 (without CMV reactivation) (P = 0.523)
2016	Ong et al[10]	Prospective, multicenter	ARDS patients on mechanically ventilated beyond day 4	271	27	Death by day 90 46 vs 28 (P < 0.01)	16 vs 9 (P < 0.01)	15 vs 8 (P < 0.01)
2015	Frantzeskaki et al[9]	Prospective, observation, multicenter	Mixed ICU, Mechanical ventilated seropositive (anti CMV IgG) positive	80	14	18 vs 22 (P > 0.05), 28 D mortality rate	32 vs 21 (NS)	27.5 vs 18 (NS)	SOFA score higher with CMV reactivation (P < 0.006), 28 d survival no difference
2016	Osawa et al[12]	Prospective, multicentre	Septic patients with BSI	100	20	20 vs 15 (P = 0.585)	27 vs 20 (P = 0.07)		VFD 15 vs 25 (P = 0.05). ICU free days 7 vs 18 (P = 0.01)
2019	Hraiech et al[17]	Retrospective, observational, single center	ARDS on VV ECMO, assessed for HSV and CMV	123	21.9	52 vs 59 (P = 0.58)	ICU LOS 29 vs 16 P < 0.01. Hospital LOS 44 vs 24 (P < 0.01)	34 vs 17.5 (P < 0.01)	Duration of ECMO 15 vs 9 (P < 0.01)
2021	Zhang et al[29]	single-center, prospective observational study	Medical ICU patients on mechanical ventialtion	71	18.3	69.2 vs 19 (P < 0.01)	ICU LOS 27 vs 12 (P < 0.01)	25 vs 10 (P < 0.01)	Hospital expenses higher in patients with CMV reactivation (P < 0.02)
2009	Kalil et al[1]	Systematic review	Included patients in ICU, 9 prospective and 4 retrospective studies	1258	17	OR: 1.93 (1.29–2.88) (P = 0.01)	ND	ND	ND
2009	Osawa et al[21]	Systematic review	13 studies, 9 prospective, 4 retrospective	ND	0-33	CMV + 29 to 100 as compared with CMV – 11 to 74 (OR: 5.7)	33 to 69 d vs 22 to 48 d (P < 0.05)	21 to 39 d vs 13 to 24 d (P < 0.05)	75% vs 50% (P = 0.04)
2017	Lachance et al[18]	Systematic review and meta-analysis	22 studies, randomized trials, observational studies (either retrospective or prospective), or case-control studies	2199	9–71	CMV reactivation was associated with a 2.5-fold increase in ICU mortality with low heterogeneity (10 studies, n = 970 patients, OR = 2.55, 95%CI = 1.87–3.47; P < 0.001)	MD 6.60 d, 95%CI = 3.09–10.12; P = 0.0002, I2 = 79%	ICU LOS was higher in CMV positive n (9 studies, n = 973 patients, MD 8.18 d, 95%CI = 6.14–10.22; P < 0.001)	Increase in nosocomial infections (OR 2.37-3.2) P < 0.05. Most common infections being ventilator-acquired pneumonia, bacteremsia, and fungal infections
2018	Li et al[3]	SR and MA	18 studies, mixed population	2398	CMV infection 27; CMV reactivation 31	All cause mortality OR: 2.16 (1.7-2.74)	ICU LOS stay (MD: 12 d)	9 d

CMV: Cytomegalovirus; APACHE: Acute physiology and chronic health evaluation; SAPS: Simplified acute physiology score; SOFA: Sequential organ failure assessment; ICU: Intensive care unit; OR: Odd’s ratio; PCR: Polymerase chain reaction; CRP: C-reactive protein; ND: No data; TNF: Tumor necrosis factor; IL: Interleukin; SICU: Surgical intensive care unit; VAP: Ventilator associated pneumonia; VFD: Ventilator free days; VV ECMO: Veno-venous extracorporeal membrane oxygenation; HSV: Herpes simplex virus; LOS: Length of stay; SR: Systematic review; MA: Meta analysis; ARDS: acute respiratory distress syndrome; IgG: Immunoglobulin G; IQR: interquartile range; ALT: alanine aminotransferase; NS: Not significant.

Table 3 Polymerase chain reaction tests for cytomegalovirus and the cut offs used in various studies

Ref.	Test	Threshold copies/ml	Threshold as per IU/mL
Papazian et al[15]	PCR		500 IU/mL whole blood
Park et al[51]	RT-PCR	> 270 copies/mL in whole blood
Hraiech et al[17]	PCR	Copy number > 500/mL CMV	“High reactivation” for viral loads greater than or equal to 1000 IU/mL or “low reactivation” for viral loads of 100–999 IU/mL
Zhang et al[29]	PCR	Copies > 500/mL
Osawa et al[12]		Copies > 500 copies/mL
Ong et al[10]			100 IU/mL

CMV: Cytomegalovirus; IU: International units; RT- PCR: Reverse transcription polymerase chain reaction.

Table 4 Therapeutic options for cytomegalovirus

No.	Drug	Mechanism	Dose	Salient features	Adverse effects
1	Ganciclovir1[63]	Nucleoside analog, needs intracellular phosphorylation to inhibit DNA polymerase, hence can develop resistance	5 mg/kg iv q12h	Preferable in life threatening disease, very high viral load and when there is a concern for inadequate gastrointestinal absorption	Severe neutropenia may become a therapy limiting adverse effect in up to 32% patients. May respond to G-CSF or GM-CSF
2	Valganciclovir1	Prodrug of ganciclovir	900 mg po q12h	Oral bioavailability is equivalent to iv ganciclovir, once-daily dosing and reduced risk of development of resistance	Neutropenia, thrombocytopenia, anemia, acute renal failure
3	Foscarnet or Phosphonoformate1	Does not require intracellular phosphorylation and therefore, retains activity against most GCV-resistant strains of CMV	90 mg/kg iv q12h	Intravenous PFA may be used under conditions of failure of GCV treatment, GCV resistance or excessive side effects such as leukopenia	PFA is nephrotoxic in 1/3rd patients, which limits its use in many critically ill patients
4	Cidofovir1	Acts directly on DNA polymerase	5 mg/kg iv once weekly	May be used as an alternative to PFA in case of GCV resistance. FDA approved only for CMV retinitis in HIV	Nephrotoxic on proximal tubular cells (Fanconi like syndrome). Pre-hydration and probenecid before the dose
5	Maribavir1[64] (Livtencity, Takeda)	Inhibition of human CMV encoded kinase pUL97: Required for viral replication	400 mg po q12h	Used in resistance to GCV, PFA, CDV	No renal or hepatic dose adjustment required. It can cause nausea, vomiting, diarrhea and neutropenia
6	Letermovir1[65] (Prevymis, Merck)	CMV viral terminase inhibitor	480 mg q24h po or iv	FDA approval for post HSCT and post renal transplant prophylaxis	Nausea, diarrhoea, vomiting, oedema. Various drug interactions requiring dose adjustments
7	Hyperimmune serum	Passive immune prophylaxis	400 U/kg on day 1, 4 and 8 and then 200 U/kg on day 12 and 16	As salvage therapy in severe recurrent CMV infections	High cost and heterogeneity of the preparation. Infusion related adverse effects like fever, shivering, rash

¹United States Food and Drug Administration approved for treatment of cytomegalovirus in immunocompromised patients.

CMV: Cytomegalovirus; G-CSF: Granulocyte colony stimulation factor; GM-CSF: Granulocyte macrophage colony stimulation factor; GCV: Ganciclovir; CDV: Cidofovir; PFA: Phosphonoformate; DNA: Deoxy ribonucleic acid; FDA: Food and drug administration; HSCT: Hematopoietic stem cell transplantation; DNA: Deoxyribose nucleic acid; HIV: Human immunodeficiency virus; iv: Intravenous; po: Per oral.