A group at the University of Pennsylvania performed a retroactive study of 29 pediatric patients hospitalized with drug hypersensitivity reactions and found that those who reactivated with HHV-6 had longer lengths of stay (11.5 days vs. 5. days) and more severe illness. HHV-6 positive patients had elevated liver gamma-glutamyltransferase (390.5 vs. 58.5 UL) and 50% had lung involvement compared to 14% of the entire study population.
All of the HHV-6 positive drug hypersensitivity patients received steroids (2-14 mg/kg) and none received antiviral therapy in spite of HHV-6 viral loads that ranged from 2,502 to 354,065 copies per ml.
The mean number of days between the start of the drug and symptoms was longer for the HHV-6 positive group (16.5 vs. 7.5 days) compared to the HHV-6 negative population.
This study is consistent with previous studies such as the 2007 study of 100 patients with drug-induced hypersensitivity in Japan that also found that patients with HHV-6 positivity (62% of the total) had a prolonged course, severe organ involvement and a late flare of symptoms (Tohyama 2007).
Unfortunately the Pennsylvania group, led by dermatologist Albert C. Yan, was not able to study one of the important concerns raised about HHV-6 positivity in hypersensitivity cases: whether steroids have a negative impact on HHV-6 positive cases. A study published last year indicated that when steroids are administered to HHV-6 positive hypersensitivity patients, the viral load increases by several logs while there is no impact on CMV or EBV reactivation in the same patients (Ishida 2014). Several studies of HHV-6 in transplant patients have shown that HHV-6 reactivates preferentially in response to high dose steroid administration (Ogata 2006, Inazawa 2015).
The fact that 50% of the HHV-6 positive patients had lung involvement was striking. Investigators from University of Washington have just revealed HHV-6 to be the cause of a significant percentage of “idiopathic” pneumonia in transplant patients, and adding steroids to these patients with occult HHV-6 positive pneumonia increased the risk of death by 6.8 fold (Seo 2015).
The University of Pennsylvania paper was accompanied by a commentary from Vincent Descamps, a French expert on viral reactivation in hypersensitivity disorders. Descamps called for a large scale study on the impact of steroid administration on patients positive for HHV-6 (Descamps 2015). He also predicted that in the future, antiviral therapy will be administered to HHV-6 positive hypersensitivity patients in conjunction with steroids.
The authors did not reveal the diagnosis of the HHV-6 positive patients or why they were tested for HHV-6, although half were taking anti-convulsant drugs. Only 14% of the patients tested were positive for HHV-6, in contrast to other studies where 45-86% were positive for HHV-6 reactivation. One reason for the difference includes the fact that HHV-6 DNA does not appear right away, often not until 2-3 weeks after the start of symptoms (Tohyama 2007). The authors of the Pennsylvania study did not reveal if testing had gone beyond a single time point; most studies define HHV-6 reactivation as either (a) a four-fold increase in antibody titers or (b) the presence of HHV-6 DNA in plasma at any point over the course of the illness.
The authors note that although steroids did not significantly improve outcome, they showed a positive trend, but only in cases that were negative for HHV-6 DNA. They were not able to study the impact of steroids on HHV-6 positive cases since all of them were treated with steroids.
For more information, read the full paper.