Delirium associated with HHV-6B reactivation in cord blood transplant patients: time for an antiviral prophylaxis trial?

A prospective study authored by Joshua Hill and Danielle Zerr determined that higher than average HHV-6B reactivation increased the odds of developing delirium after cord blood transplantation (CBT) by almost three fold. Patients with DNA loads in the top quartile had a 4.5 fold increase in delirium. The study also demonstrated that intensified antiviral prophylaxis may mitigate HHV-6B reactivation.

In an article published in Bone Marrow Transplantation, the authors described 35 CBT patients whose HHV-6 levels were routinely monitored several times per week post-transplant. In addition, the patients underwent comprehensive delirium assessment 3X weekly through day 56, and weekly until day 84 post-transplant. HHV-6B reactivation was detected in 66% of patients and 11 (31%) patients experienced an episode of delirium lasting a median of 3 days. Subsequent statistical analysis demonstrated that delirium episodes were significantly more likely in patients with HHV-6B levels above the median.

Of two patients with delirium and concurrent CSF sampling, only one had evidence of HHV-6B in the plasma and cerebrospinal fluid . Although there are many other causes of delirium in this patient population, the group points out that HHV-6 DNA detection in liquid compartments (i.e. blood, CSF, BAL) may be insufficient for identifying HHV-6B end-organ disease. They explain that HHV-6B can persist in brain tissue at very high viral loads, with little in the plasma or CSF (Fotheringham 2007, Wainright 2001). Similarly, HHV-6 has been shown to cause chronic hepatitis and fatal myocarditis with no associated viral detection in the blood (Buyse 2013, Leveque 2011).

Approximately half of the patients were given intensified CMV prophylaxis consisting of ganciclovir during conditioning, followed by valacyclovir (Valtrex) at 2 grams every 8 hours for 100 days (vs Valtrex 500 mg twice daily). These patients had about a 50% reduction in the hazard of developing HHV-6 reactivation above the median level in the population. A smaller 1996 study also showed that high dose valacyclovir (2 grams every 6 hours) reduced the percentage of patients who reactivated HHV-6B (33% reactivation rate in the treated group vs. 82% patients who were not treated prophylactically).

Of interest, HHV-6B was found in the CSF of two patients who had headache but not delirium. In a study published earlier this year, the University of Washington group presented a retrospective analysis of 51 HHV-6 positive spinal fluid samples from HSCT patients and found that the majority (37) were positive for HHV-6 alone, while the rest had a co-infection (5), drug toxicity (3) or transient symptoms (6).

Danielle Zerr

Danielle Zerr, Professor at the University of Washington and Division Chief of Pediatric Diseases at Seattle Children’s Hospital has been at the forefront of looking at HHV-6B as a cause of delirium and cognitive dysfunction.

The authors maintain that delirium could be a result of either direct tissue-level reactivation and/or indirect effects of systemic reactivation (i.e. pro-inflammatory cytokines). They note that the same inflammatory cytokines that arise in transplant patients with delirium can also be found in ICU patients with delirium (Sobbi 2014). HHV-6 also reactivates in critically ill patients (Razonable 2002, Lopez Roa 2015).

The study expanded upon Zerr’s previously groundbreaking work, published by Blood in 2011, which found a significant increased risk of cognitive decline and delirium to be associated with HHV-6 reactivation after transplantation. Delirium is a significant issue in transplantation because patients who develop delirium in the first 4 weeks are more likely to develop fatigue at six months, depression at one year, and worse memory, cognitive and executive functioning at both 6 months and 1 year (Basinksi 2010). Unlike the 2011 report, the current study did not address cognitive decline associated with HHV-6B reactivation.

Another recent Japanese study examined 13 viruses in 105 allogeneic stem cell transplant patients and found that of the 7 patients that developed cognitive dysfunction, 6 were positive for HHV-6B alone (Inazawa 2015). Four were determined to have HHV-6 encephalitis.

The University of Washington investigators conclude that larger trials are needed to explore prophylaxis against HHV-6B in cord blood transplant patients.

For more information, read the full paper.