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"The Issue of CMV Reactivation in Serpositive Sepsis Patients: No to Prophylaxis" by Steven P. LaRosa, M.D.




Cytomegalovirus (CMV) is a member of the Herpesviridiae family and is endemic throughout the world. Approximately 60% of adults are seropositive for past CMV infection. Reactivation of CMV is a source of significant morbidity in immunocompromised hosts. CMV can cause direct organ injury, activate the coagulation cascade as well as act as an endogenous immunosuppressant leading to secondary bacterial, fungal and viral infections. In the immunocompetent critically ill ICU population, CMV viremia is found in approximately 30%  of CMV seropositive patients and is associated with a poor outcome. It is unclear if CMV leads to poor outcome or is a disease severity marker.

In the current issue of JAMA 2017; 318 (8): 731-740 Ajit Limaye and colleagues begin to address in the question. They performed a double-blind, placebo controlled trial in patients who had either sepsis or severe trauma and were seropositive for past CMV infection. A total of 160 patients were randomized to receive prophylactic Ganciclovir, Valganciclovir or placebo. The primary endpoint was reduction in IL-6 which is thought to be an important mediator in CMV reactivation. Secondary endpoint included occurrence of CMV reactivation, effects on the need for mechanical ventilation, ICU length of stay, incidence of secondary infections and mortality.
The primary analysis did not demonstrate any significant difference in IL-6 levels with Gancioclovir prophylaxis. Ganciclovir prophylaxis however had a statistically significant effect of the incidence of CMV reactivation with a rate of 39% in the placebo group and 12% in the treatment arm; p=< 0.001. In the overall group there was not a significant difference in mortality or secondary infections. The ganciclovir arm had 3 additional ventilator-free days; a finding that reached the border of statistical significance.

The data from this trial would indicate that Ganciclovir prophylaxis should not at this time be given as prophylaxis to all sepsis patients or even the subpopulation of sepsis patients who are CMV prophylaxis. A clinical trial that still should be performed is RCT of "pre-emptive" Ganciclovir in sepsis patients who demonstrate CMV reactivation as indicated by a positive PCR data. The literature would indicate that this would occur in approximately 30% of the 60% of patients who are seropositive for CMV or 18% of the total population with sepsis. This is not an insignificant number of patients. A meta-analysis by Andre Kalil and colleagues (Crit Care Med 2009 Aug; 37(8):2350-8.) revealed an all-cause mortality of 39% in patients with CMV viremia versus those without 27%. A clinical trial of approximately 500 patients would likely be needed to answer this critical question.




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