Cytomegalovirus in the Critically Ill

OVERVIEW

Cytomegalovirus (CMV) is a human herpesvirus (HHV) that rarely causes significant disease in immunocompetent people but is an important cause of illness in the immunocompromised

• CMV is found in 50% to 80% of otherwise healthy adults (Limaye et al, 2017)
• the importance of reactivation of CMV  in “non-immunosuppressed” critically ill patients (such as severe trauma, sepsis, shock, burns, and cirrhosis) is controversial (Papazian et al, 2016; Limaye et al, 2010)
• infection may or may not lead to CMV-related disease and active infection may be due to either primary infection or reactivation of latent infection
• latent infection occurs in multiple sites, including the lung ((Limaye et al, 2017)

RISK FACTORS

Risk factors for CMV disease include ((Bersten et al, 2014;Papazian et al, 2016; Limaye et al, 2010):

• transplant recipients
  • allogenic stem cell > lung > pancreatic > liver, heart, renal
  • negligible risk if both donor and recipient are CMV seronegative
  • high risk of disease if seropositive donor and seronegative recipient (~70% overall)
  • high risk of infection and moderate risk of disease if seropositive recipient (~70% and ~20%, respectively, overall), regardless of donor status
  • higher risk if treatment required for acute rejection
• advanced acquired immunodeficiency syndrome (AIDS) (typically  CD4 T cell count < 50/mL)
• steroid use
• mechanical ventilation
• bacterial pneumonia and sepsis
• red cell transfusion (via immunomodulation not transmission)
• burns

CLINICAL FEATURES

Can cause:

• pneumonitis
• multiorgan dysfunction (especially hepatic and renal)
• gastrointestinal disease
  • oesophagitis
  • colitis, toxic megacolon
  • biliary disease
• meningoencephalitis
• Guillain-Barre syndrome (GBS)
• adrenal insufficiency
• retinitis
  • usually presents with unilateral blurred vision, visual field loss, or ‘floaters’
  • diagnosed fundoscopy by an opthalmologist
• Thrombocytopaenic Thrombotic Purpura (TTP)

INVESTIGATIONS

Investigations for CMV

• antigenemia
  • direct detection of CMV protein pp65 in white blood cells (WBCs) using monoclonal antibodies
  • sensitive but requires sufficient WBCs in peripheral blood
• PCR assays
  • high sensitivity and rapid turnover time
  • can be used to monitor response to therapy and detect antiviral resistance
• tissue biopsy
  • generally required for a definitive diagnosis of tissue involvement
• viral cultures
  • low sensitivity and time consuming
  • now obsolete

MANAGEMENT

First line antiviral agent for serious active infection (usually in the context of immunocompromise)

• Ganciclovir
  • 5 mg/kg IV, 12-hourly for 14 days
  • Cytotoxic drug handling and administration precautions must be observed
  • Usually infused over 60 minutes
  • Adjust dosing if renal impairment is present

Other options if ganciclovir is contra-indicated

• foscarnet
  • 90 mg/kg IV, 12-hourly or 180 mg/kg/day by continuous IV infusion for 14 days
• valganciclovir
  • 900 mg orally, 12-hourly for 14 to 21 days
  • may be used as first line therapy for CMV retinitis in AIDS
  • sometimes used as step-down therapy following response to IV ganciclovir
• cidofovir
  • 5 mg/kg IV weekly for 2 weeks
  • administer with probenecid
  • avoid if renal disease

Other information

• Intraocular implants or injections can be used by ophthalmologists in the management of CMV retinitis
• Maintenance therapy is sometimes required in patients with chronic active immunosuppression
• Transplant centers have treatment protocols for post-operative transplant recipients based on donor and recipient seropositivity.
• Treatment to prevent reactivation is not currently recommended in other patient groups
  • Limaye et al (2017) in a randomised controlled trial found that treatment of sepsis patients with ganciclovir did not affect levels of IL6, although there was a reduction in CMV reactivation as a secondary outcome.

OUTCOME

CMV infection is associated with (Limaye et al, 2010; Ong et al, 2016):

• increased organ dysfunction (liver and renal)
• prolonged ICU stay
• increased duration of mechanical ventilation
• increased incidence of nosocomial infection
• increased mortality

References and Links

Journal articles and textbooks

• Al-Omari A, Aljamaan F, Alhazzani W, et al. Cytomegalovirus infection in immunocompetent critically ill adults: literature review. Annals of intensive care. 2016; 6(1):110. [pubmed]
• Bonalumi S, Trapanese A, Santamaria A, et al. Cytomegalovirus infection in pregnancy: review of the literature. J Prenat Med. 2011 Jan;5(1):1-8. [pubmed] [article]
• Griffiths P, Baraniak I, Reeves M. The pathogenesis of human cytomegalovirus. The Journal of pathology. 2015; 235(2):288-97. [pubmed]
• Jain M, Duggal S, Chugh TD. Cytomegalovirus infection in non-immunosuppressed critically ill patients. J Infect Dev Ctries. 2011 Aug 12;5(8):571-9. Review.  [pubmed] [article]
• Kalil AC, Florescu DF. Is cytomegalovirus reactivation increasing the mortality of patients with severe sepsis? Crit Care. 2011;15(2):138. [pubmed] [article]
• Limaye AP, Stapleton RD, Peng L, et al. Effect of Ganciclovir on IL-6 Levels Among Cytomegalovirus-Seropositive Adults With Critical Illness: A Randomized Clinical Trial. JAMA. 2017; 318(8):731-740. [pubmed]
• Limaye AP, Boeckh M. CMV in critically ill patients: pathogen or bystander? Rev Med Virol. 2010 Nov;20(6):372-9. doi: 10.1002/rmv.664. Review. [pubmed] [article]
• Limaye AP, Kirby KA, Rubenfeld GD, Leisenring WM, Bulger EM, Neff MJ, Gibran NS, Huang ML, Santo Hayes TK, Corey L, Boeckh M. Cytomegalovirus reactivation in critically ill immunocompetent patients. JAMA. 2008 Jul 23;300(4):413-22. [pubmed] [article]
• Ong DS, Spitoni C, Klein Klouwenberg PM, et al. Cytomegalovirus reactivation and mortality in patients with acute respiratory distress syndrome. Intensive care medicine. 2016; 42(3):333-41. [pubmed]
• Osawa R, Singh N. Cytomegalovirus infection in critically ill patients: a systematic review. Crit Care. 2009;13(3):R68. doi: 10.1186/cc7875. Epub 2009 May  14. Review. [pubmed] [article]
• Papazian L, Hraiech S, Lehingue S. Cytomegalovirus reactivation in ICU patients. Intensive care medicine. 2016; 42(1):28-37. [pubmed]