Poor Outcome in ICU Patients with HHV-6 & CMV

Intensive care (ICU) patients with co-infections of HHV-6 and CMV are 7.5x more likely to die or have an extended stay in the hospital (95% confidence interval, 1.9-29.9), according to investigators at the University of Washington who studied viremia in 115 acutely ill adults.

Ajit Limaye

Dr. Ajit Limaye, Director, Solid Organ Transplant, Infectious Disease Program, University of Washington

23% of ICU patients reactivated with HHV-6 and of those, 70% also reactivated with CMV. Surprisingly, the median duration of viremia for HHV-6 was only 1 day, compared to 14 days for CMV. The highest rate of viral reactivation was found in burn unit patients, with HHV-6 and CMV rates of reactivation 40% and 55% respectively.

The study was led by Ajit Limaye, Professor and Director of Solid Organ Transplant Infectious Disease Program at University of Washington. Joshua Hill, MD and Paula Roa, PhD,  were joint first authors on the study. The authors call for treatment or prevention trials to explore a possible causal link between viral reactivation and adverse outcomes in ICU patients. They also speculate that HHV-6 might contribute to ICU delirium and long-term cognitive impairment in these patients. A previous study at UW by Danielle Zerr showed a link between HHV-6 reactivation and delirium in transplant patients (Zerr 2011). HHV-6 and CMV are closely related viruses and both suppress cellular immunity, which in turn increases the risk of secondary infections. This immune suppression  could explain the association of these viruses with higher mortality and longer length of stay.

Dr.’s Hill and Limaye commented that “the findings are very interesting and hypothesis generating. Additional studies exploring the impact of prophylactic or preemptive therapies for betaherpesviruses, as well as mechanisms by which these viruses may contribute to the observed findings, will be important next steps.”

This study represented a re-analysis of samples collected for a previous study of CMV reactivation in 120 critically ill patients. Patients with CMV viremia (33%) in that study were found to have an increased risk of death or an extended hospital stay (Limaye 2008). The UW group used a very sensitive assay for HHV-6 that would detect 25 copies per ml in plasma.

The University of Washington (UW) investigators tested 8 of the positive samples and determined that they were all HHV-6B. This result differs from a study done in 2002 by investigators at Mayo Clinic that found HHV-6 in 54 of 101 critically ill immunocompetent patients , where 53 of the samples were typed as HHV-6A (Razonable 2002). The Mayo clinic study analyzed blood collected on the 4th day in the ICU, which may have been the reason they found only 1 out of 101 positive for CMV. The Mayo Clinic group also studied peripheral blood lymphocytes while the UW group tested  plasma. The Mayo Clinic ICU patients were immunocompetent medical, surgical or trauma patients, while the UW patients also included burn ICU patients.


Joshua Hill, MD, PhD, Infectious Disease Sciences Program, Vaccine & Infectious Disease, University of Washington Fred Hutchinson Cancer Research Center

A recent study from France demonstrated that EBV reactivation is associated with increased mortality, a longer hospital stay and increased time using mechanical ventilation, but HHV-6 was not assessed in that study (Libert 2015). A 2001 study from France found that 54% of 46 ICU patients with multi-organ failure had HHV-6 reactivation by PCR in the serum, although it did not adversely affect morbidity or patient outcome (Desachy 2001). Similarly, a study from Greece showed that CMV alone reactivated in 14% of critically ill patients but did not affect clinical outcome (Frantzeskaki 2015).

Viral reactivation of HHV-6, CMV, EBV and HSV1 also correlate with severity of illness in patients with sepsis (Walton 2014).

For more information on the University of Washington study, read the full paper.