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 erythmea with high fever and multi-organ involvement, especially liver dysfunction. However, the specific mechanisms for viral reactivation and modification of the clinical features remain unclear.

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). Preliminary results from a study in France suggest that the immune response observed in DRESS patients is principally directed against human herpesviruses, especially HHV-6 (Descamps 2006). Another study sought to determine whether herpesviruses reactivate from latency in an obligate order in the course of DIHS, and whether they contribute to the clinical manifestations of the syndrome.

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). Finally, a group in Japan retrospectively analyzed reports of DIHS published in medical journals and found that nearly 84% of DIHS patients had HHV-6 reactivation by increase of HHV-6 IgG and/or increase of HHV-6 DNA in the peripheral blood (Aihara 2003).


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

DIHS

Ishida 2014 The dynamics of herpesvirus reactivations during and after severe drug eruptions: their relation to the clinical phenotype and therapeutic outcome
Fujita 2014 Serum level of HMGB1 is preferentially high in DIHS/DRESS
Uno 2014 TNF-a as a useful predictor of HHV-6 reactivation and indicator of the disease process in DIHS/DRESS
Prasad 2013 Activation of human herpesvirus replication by apoptosis
Uhara 2012 Clinical course of DIHS treated without systemic corticosteroids
Pritchett 2012 The link between hypersensitivity syndrome reaction development and HHV-6 reactivation
Tohyama 2011 New aspects of Drug-induced Hypersensitivity Syndrome
Gentile 2010 Is the drug-induced hypersensitivity syndrome (DIHS) due to human herpesvirus 6 infection or to allergy-mediated viral reactivation? Report of a case and literature review
Hashizume 2009 Emergence of circulating monomyeloid precursors predicts reactivation of human herpesvirus-6 in drug-induced hypersensitivity syndrome
Tohyama 2007 Association of human herpesvirus 6 reactivation with the flaring and severity of drug-induced hypersensitivity syndrome
Shiohara 2007 A Complex Interaction Between Drug Allergy and Viral Infection
Yoshikawa 2006 Human herpesvirus 6 reactivation and inflammatory cytokine production in patients with drug-induced hypersensitivity syndrome.
Kano 2006 Hypogammaglobulinemia as an early sign of drug-induced hypersensitivity syndrome
Inaoka 2005 Innate immunity and hypersensitivity syndrome
Nakashima 2005 Drug-Induced Hypersensitivity Syndrome Associated with Transient Hypogammaglobulinaemia and Increase in Serum IgE Level
Kano 2004 Association Between Anticonvulsant Hypersensitivity Syndrome and Human Herpesvirus 6 Reactivation and Hypogammaglobulinemia
Aihara 2003 Carbamazepine-induced hypersensitivity syndrome associated with transient hypogammaglobulinaemia and reactivation of human herpesvirus 6 infection demonstrated by real-time quantitative polymerase chain reaction.

DRESS

Descamps 2013 Saliva PCR assay for detection and follow-up of herpesvirus reactivation in patients with DRESS
Blumenthal 2012 The importance of vancomycin in DRESS syndrome
Picard 2010 Drug reaction with eosinophilia and systemic symptoms (DRESS): a multiorgan antiviral T cell response
Mardivirin 2009 Amoxicillin-induced flare in patients with DRESS (Drug Reaction with Eosinophilia and Systemic Symptoms): report of seven cases and demonstration of a direct effect of amoxicillin on Human Herpesvirus 6 replication in vitro
Eshki 2009 Twelve-year analysis of severe cases of drug reaction with eosinophilia and systemic symptoms: a cause of unpredictable multiorgan failure
Descamps 2006 Association of hypogammaglobulinemia with DRESS (Drug Rash with Eosinophilia and Systemic Symptoms).
Descamps 2001 Association of Human Herpesvirus 6 Infection With Drug Reaction With Eosinophilia and Systemic Symptoms

Stevens-Johnson Syndrome (SJS)

Hirahara 2010 Differences in immunological alterations and underlying viral infections in two well-defined severe drug eruptions
Peppercorn 2010 High-Level Human Herpesvirus-6 Viremia Associated With Onset of Stevens-Johnson Syndrome: Report of Two Cases
Teraki 2010 Stevens–Johnson syndrome and toxic epidermal necrolysis due to anticonvulsants share certain clinical and laboratory features with drug-induced hypersensitivity syndrome, despite differences in cutaneous presentations

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