Numerous studies have linked the reactivation of HHV-6 to Drug-Induced Hypersensitivity Syndrome (DIHS)/drug rash with eosinophilia and systemic symptoms (DRESS), an uncommon but severe cutaneous adverse drug reaction characterized by acute widespread erythema with high fever and multi-organ involvement, especially liver dysfunction. Retrospective analysis of reports published in medical journals found that nearly 84% of DIHS/DRESS patients had HHV-6 reactivation by increase of HHV-6 IgG and/or increase of HHV-6 DNA in the peripheral blood (Aihara 2003), and the HHV-6 cellular entry receptor CD134 has been found to be preferentially expressed on T cells of DIHS/DRESS patients (Miyagawa 2016), which may contribute to the intense reactivation. The virus can generally be detected in the blood 2-3 weeks after onset, which is not the case in other severe cutaneous adverse drug reactions, such as toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS). In fact, reactivation of HHV-6 is among the criteria for the diagnosis of DIHS/DRESS in Japan.
The real time PCR results from patients with severe DIHS demonstrated that herpesviruses reactivate in a sequential order as described in patients with graft-versus-host disease (GVHD); the sequential herpesvirus reactivation is coincident with the various clinical manifestations in patients with DIHS (Kano 2004). Studies report a strong association between the reactivation of HHV-6 and a more severe course (Tohyama 2007, Pritchett 2012), and the active virus has been found in several dysfunctional organs of individuals with DRESS, including the liver, kidneys, heart, and lymph nodes, as well as the bone marrow and cerebrospinal fluid (CSF) (Mine 2014, Descamps 2014, Eshki 2009, Miyashita 2016, Hagiya 2016, Fujino 2002, Mennicke 2009). Moreover, several cases (Descamps 2014, Eshki 2009, Hagiya 2016, Moling 2012) have reported clinical improvement after the administration of valganciclovir.
At this time, the specific mechanisms for viral reactivation and modification of the clinical features remain unclear. It is thought that HHV-6 reactivates in response to the altered immune environment that arises during the adverse drug reaction, and consequently, a strong anti-viral immune response is triggered to combat the infection. In turn, immune cells attack the cells containing HHV-6 and infiltrate the infected organs, causing widespread damage (Shiohara 2006, Cho 2017). Preliminary results from France suggest that in DRESS patients, there is an immune response directed against human herpesviruses (Picard 2010, Descamps 2006), and characterization of the virus-specific immune response during DIHS/DRESS is ongoing. Direct effects of HHV-6 reactivation may also be at play in DIHS/DRESS, and a small in vivo study in Japan demonstrated that HHV-6 reactivation induces synthesis of proinflammatory cytokines, specifically elevations of TNF-a and IL-6, which may modulate the clinical features of the syndrome (Yoshikawa 2006).
Drugs Associated with HHV-6 Reactivation
IN VIVO (DIHS, DRESS, AHS, SJS, and TEN)
| Drug | Associations | References | Notes |
| allopurinol | DIHS, DRESS, SJS | 1-7 | Enzyme inhibitor used for gout; may cause a drop in circulating B cells 8. |
| carbamazepine | AHS, DIHS, DRESS, SJS, TEN | 3, 9-21 | Anticonvulsant and HDAC inhibitor. Associated with transient hypogammaglobulinemia 14, 17. |
| dapsone | AHS, DIHS, DRESS | 3, 22 | Antibiotic and anti-malarial drug. |
| ibuprofen | DIHS, DRESS | 12, 23 | Non-steroidal anti-inflammatory drug; one case was in association with diclofenac 23. |
| lamotrigine | AHS, DIHS, DRESS | 24, 25 | Anticonvulsant. |
| mexiletine | DIHS | 3, 26, 27 | Class 1B anti-arrhythmic. |
| minocycline | DIHS, DRESS | 5, 28, 29 | Broad spectrum tetracycline antibiotic. |
| naproxen | DRESS | 30 | Non-steroidal anti-inflammatory drug that inhibits both COX-1 and COX-2 enzymes. |
| phenytoin | AHS, DIHS | 10, 31-33 | Cross-sensitive with carbamazepine and phenobarbital 18. |
| phenobarbital | AHS, DIHS, DRESS | 3, 10, 28, 31, 32, 34-37 | Barbituate and anticonvulsant known to induce EBV in Raji cells; cross-sensitive with carbamazepine and phenytoin 18. |
| sodium valproate | AHS, DIHS | 38 | Anticonvulsant, HDAC inhibitor and rare cause of DIHS. Three cases have been reported, but in two of them HHV-6 was not tested 39, 40. |
| sulfasalazine | DIHS, DRESS, | 30, 41-43 | Anti-inflammatory that is not an immunosuppressant; used in inflammatory bowel disease and rheumatoid arthritis. |
| trichloroethylene | DIHS | 44, 45 | HDAC inhibitor and industrial solvent previously used as an anesthetic and inhaled obstetrical analgesic. |
| trimethoprim-sulfamethoxazole | DIHS, DRESS | 46, 47 | Sulfonamide antibiotic. |
| vancomycin | DRESS | 48, 49 | In one case teicoplanin was also reactive 49. |
| zonisamide | AHS, DIHS, TEN | 3, 10, 50, 51 | Sulfonamide anticonvulsant. |
IN VITRO
| Drug | References | Notes |
| 12-O-tetradecanoylphorbol-13-acetate (TPA) | 52-54 | Diester of phorbol and potent tumor promoter, used in laboratories to activate herpesviruses, stimulate division of B cells, and activate signal transduction enzyme protein kinase C. |
| amoxicillin | 5 | β-lactam antibiotic. |
| calcium ionophore, A23187 | 54 | Ion carrier also known as calimycin or calcium ionophore; used in the laboratory to reactivate latent herpesviruses. |
| hydrocortisone | 53, 55 | Cortisol, a steroid hormone produced by the adrenal gland; used in the laboratory to reactivate herpesviruses. |
| sodium n-butyrate | 54 | HDAC inhibitor; used in the lab to alter gene expression or activate herpesviruses. |
| trichostatin A | 53 | HDAC inhibitior; closely related Vorinostat is FDA approved for the treatment of cutaneous T cell lymphoma. |
| valproic acid and carbamazapine | 56 | HDAC inhibitors; evidence conflicting because valproic acid was also shown to inhibit HHV-6B replication in one of three cell lines 57. VPA inhibits EBV, but enhances HHV-8 replication in vitro 58. |
Key Papers: HHV-6 & Drug-Induced Hypersensitivity Syndrome
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