TY - JOUR
AU - MD, Bruce A. Cairns,
AB - Abstract The pathogenesis of Stevens-Johnson syndrome (SJS) remains obscure, but it has been associated with various infectious agents, including members of the herpesvirus family. We present the first report of high-level human herpesvirus-6 viremia at the onset of SJS, suggesting a possible new association. This finding supports the need for further investigation into the possible relationship between human herpesvirus-6 and SJS, which may illuminate the pathogenesis of SJS and bring us closer to achieving enhanced prevention and treatment of this rare disease. Stevens-Johnson syndrome (SJS) is a rare, idiopathic, and poorly understood immunologically mediated mucocutaneous process that is part of a continuum with bullous erythema multiforme (EM) and toxic epidermal necrolysis syndrome (TENS)1 although EM remains somewhat distinct from SJS/TENS based on a much stronger association with infectious inciting agents. The pathogenesis of SJS is thought to be initiated by an immune response to an antigenic complex formed by drug metabolites or microorganisms. Genetic susceptibility has also been implicated with an increased incidence in persons with the HLA-B12 allele.2 It has been associated with numerous drugs and infectious agents, including members of the herpesvirus family such as herpes simplex virus (HSV), cytomegalovirus (CMV), and varicella-zoster virus.3,–6 EM is strongly associated with HSV types I and II, with HSV-encoded proteins identified in affected epidermis and HSV DNA detected in target lesions.7,–9 Human herpesvirus (HHV)-6 was first identified in 1986 and quickly reported as the cause of childhood roseola infantum (sixth disease, exanthem subitum).10,–14 Similar to other herpesviruses, HHV-6 remains latent in host cells after primary infection but can reactivate when the immune system is suppressed. In recent years, HHV-6 has been recognized as an emerging pathogen associated with pneumonitis and encephalitis after stem cell transplantation15,–17 and may be associated with drug-induced hypersensitivity syndrome.18 Other novel associations continue to be explored.19,–21 In this report, we describe two immunocompetent patients with SJS associated with high-level HHV-6 variant B viremia at onset of clinical presentation. Given its ubiquitous nature, HHV-6 may account for a proportion of idiopathic cases of SJS. Case 1 An 18-year-old woman with a history of recurrent oral and genital HSV outbreaks presented with fever, malaise, and myalgias, and subsequently developed 60% TBSA involvement with target lesions, extensive erythematous plaques, bullae involving her face, neck, arms, chest, and abdomen, and proximal extremities as well as epithelial defects and pseudomembrane involvement of both conjunctivae. She had extensive orolabial and genital mucosal surface denudement and complete epidermal detachment of at least 10% of the skin surface of her chest, abdomen, back, and face consistent with SJS/TENS based on standard classification.1 Her long-standing medications included valacyclovir, promethazine, synthroid, belladonna, and orthotricycline. She had not taken any newly prescribed medications. A biopsy of the skin demonstrated vacuolar interface dermatitis with a few apoptotic keratinocytes and focal subepidermal cleft formation consistent with EM or early SJS. There was no viral cytopathic effect noted. Corticosteroids were not administered. Diagnostic studies included negative urine, blood, and genital tract bacterial cultures, antistreptococcal antibodies, Mycoplasma serologies, HIV enzyme-linked immunosorbent assay and polymerase chain reaction (PCR), CMV and Epstein-Barr virus (EBV) plasma PCR tests, and monospot test. HSV type 1 and 2 PCR tests from genital tract and inner thigh erosion samples were negative. However, HHV-6 plasma PCR showed high-level viremia (ViraCor Laboratories, Lee's Summit, MO) of 115,000 DNA copies/ml (plasma sample obtained before first intravenous immunoglobulin [IVIG] administration). Genotyping by real-time PCR identified HHV-6 variant B. Initial serologies (obtained after the initiation of IVIG) showed an IgG of 1:320 and IgM <1:20 (Focus Diagnostics, Cypress, CA). Repeat serologies at 4 weeks reported IgG 1:640 and IgM <1:20. Surprisingly, she continued to be viremic at weeks 2, 4, and 8 with values of 19,100 copies/ml, 18,300 copies/ml, and 20,400 copies/ml, respectively. At week 14, HHV-6 level had dropped to 2700 DNA copies/ml and IgG was 1:10 and IgM <1:20. Sequential EBV and CMV plasma DNA PCR testing remained negative. Case 2 A 64-year-old woman presented with 5 days of progressive sore throat, eye irritation, and malaise and developed target lesions on a background of symmetric diffuse (∼80% TBSA) erythematous papules and confluent erythema that progressed to extensive epidermal detachment (∼50% BSA) as well as mucosal erosions involving her conjunctiva and oropharynx. Punch biopsy confirmed vacuolar interface and subepidermal vesicular dermatitis with focal full-thickness epidermal necrosis consistent with SJS (Figure 1). Approximately 1 month before this, she was treated for a flare of gout with a 2-week course of prednisone and allopurinol, a drug associated with SJS/TENS. Long-standing medications included hydrochlorothiazide, dehydroepiandrosterone, glucosamine, aspirin, and ezetimibe/simvastatin. Corticosteroids and IVIG were not administered. Figure 1. View largeDownload slide Vacuolar alteration of the dermal epidermal interface associated with scattered apoptotic keratinocytes is present on the left side of the image with progression to subepidermal cleft formation and full-thickness epidermal necrosis on the right side of the image (original magnification ×200). Figure 1. View largeDownload slide Vacuolar alteration of the dermal epidermal interface associated with scattered apoptotic keratinocytes is present on the left side of the image with progression to subepidermal cleft formation and full-thickness epidermal necrosis on the right side of the image (original magnification ×200). Initial diagnostic evaluation included negative blood and urine cultures, rapid influenza A/B antigen detection, rapid group A Streptococcus antigen detection, antistreptococcal antibodies, and EBV and CMV plasma PCR tests. Initial HHV-6 qualitative plasma PCR was negative on hospital day 2 in the setting of extensive fluid resuscitation due to insensible losses and hypotension, however, quantitative testing on hospital day 6 demonstrated 1500 DNA copies/ml and by day 8 was 131,000 DNA copies/ml. Follow-up HHV-6 viral load on hospital day 21 was 400 copies/ml. A lip erosion tested negative for HSV 1/2 by PCR but tested positive for HHV-6 by PCR. Genotype testing confirmed HHV-6 variant B. Initial serologies showed HHV-6 IgG 1:640 and IgM <1:20. Convalescent serologies confirmed HHV-6 IgG 1:1280 and IgM <1:20. Sequential EBV and CMV plasma PCR tests remained negative. In both patients, baseline serology testing for EBV and CMV was consistent with previous exposure and latency (+EBV viral capsid IgG, +CMV IgG), but serial plasma PCR testing for reactivation of these other herpesviruses remained negative. The decision was made to withhold antiviral therapy targeted at HHV-6 based on the unclear significance of this association and concern about added medication toxicity. Both patients survived but with substantial morbidity. In case 1, the patient suffered corneal scarring with permanent blindness, oropharyngeal stricture, and vaginolabial fusion; in case 2, the patient had a prolonged hospitalization complicated by pseudomembranous conjunctivitis, pseudomonal pneumonia, and multisystem organ failure. She was discharged with tracheostomy and feeding tube in place and continues to require hemodialysis. DISCUSSION The ability of herpesviruses to lay dormant in host tissue after primary infection requires a functioning immune system to prevent reactivation. When there is a disruption or alteration in cell-mediated immunity, either because of the use of immunosuppressive agents, aging, and alteration in cytokine expression (sepsis, burn injury, and drug or allergic reaction) or development of an immunosuppressive disorder (eg, HIV/AIDS and malignancy), herpesviruses can replicate and cause an array of medical conditions.22 The relatively recent availability of nucleic acid amplification testing has identified many new conditions associated with herpesviruses. In this report, we identified high-level HHV-6 viremia temporally associated with the onset of SJS, a condition primarily associated with medications but also with herpes family viruses and other infectious agents. In case 1, it is unclear whether this represented primary or reactivated infection. The patient was younger, had no clear medication precipitant, and her HHV-6 viral load remained high for several weeks, which may favor primary infection (serologies were confounded by the administration of IVIG; the IVIG administered to the patient was not tested for the presence of HHV-6 viral particles by PCR or culture, however, standard manufacturing processes for IVIG incorporate rigorous viral elimination procedures23). However, reactivation still remains more likely based on seroepidemiologic data supporting greater than 90% seroprevalence of HHV-6 by the age of 2 years.24 A third possibility is congenital chromosomally integrated HHV-6 that can occur in about 1% of the population and represents HHV-6 DNA fragments in every nucleated cell. Although the decline in her viral load over time and the use of acellular (plasma) testing make this unlikely, specific testing for chromosomal integration using whole blood or hair follicles was not performed.25,26 In case 2, serologic data support reactivation disease. She had received allopurinol as well as a course of steroids before her illness, which could have precipitated reactivation of HHV-6. Of interest, her lip erosion was positive for HHV-6 by PCR, however, HHV-6 is commonly shed in saliva and could have contaminated the lesion. No viral cytopathic changes were visualized on skin biopsy in both cases, but HHV-6 DNA/RNA testing and protein expression (gp116/54/64) by routine immunohistochemistry described by Fotheringham et al27 were not performed. Approximately 10 subsequent patients with SJS/TENS at our institution, including pediatric patients (looking for an association with primary HHV-6 infection), have tested negative for HHV-6 viremia using the same diagnostic methods, suggesting HHV-6 as a rare etiology of SJS. Although these two patients presented with high-level HHV-6 type B viremia, a causal role for HHV-6 in the development SJS cannot be explained without further investigation. Detection of HHV-6 viremia in nonimmunocompromised patients with acute illness was described in one study of patients with multisystem organ failure in which 54% of the patients had detectable serum HHV-6 DNA by PCR, but quantification of viral load was not performed, and HHV-6 genotype was not reported.28 A subsequent study of critically ill patients found a 53% rate of HHV-6 viremia at time of admission to an intensive care unit, but the nucleic amplification technique used in that study included peripheral blood leukocytes, which can be complicated by chromosomally integrated HHV-6 DNA.29 In that study, all but one case was typed as HHV-6 variant A.30 A recent report of low-grade HHV-6 viremia in association with zonisamide-related TENS also used whole blood testing, which may be confounded by amplification of latent HHV-6 in peripheral monocytes, and in that case, HHV-6 DNA was not found early in the disease course but was documented at day 22 of hospitalization. CMV and EBV reactivations were not reported to look for evidence of other herpesvirus reactivation.31 A possible role for HHV-6 in the pathogenesis of dermatologic conditions has previously been explored. In a study of drug-induced hypersensitivity syndrome, Tohyama et al18 showed that anti-HHV-6 IgG titers increased in 62% of patients, and HHV-6 viremia was detected in 18% of patients (range, 120–2,400,000 copies/ml) between 10 and 27 days after the onset of symptoms and was associated with more severe organ involvement, prolonged illness including flaring of fever and hepatitis, and mortality in comparison with those patients without evidence of HHV-6 reactivation. The authors postulate that potent drug-reactive T cells act similarly to alloreactive T cells after organ transplantation and may drive HHV-6 reactivation. Interestingly, they also report no cases of HHV-6 reactivation among the 10 patients diagnosed with SJS or TENS in their discussion, and a recent investigation in China on the etiology of SJS found no HHV-6 reactivation among 16 patients surveyed using DNA PCR.32 Therefore, we report the first two cases of SJS associated with high-level HHV-6 viremia at onset of disease. Our report is limited, based on data from two distinct patients, one of whom had allopurinol as a likely drug precipitant (case 2) and the other had IVIG administration (case 1) precluding conclusive serologic interpretation. However, the demonstration of high-level viremia determined by quantitative real-time PCR testing in the first week of hospitalization is compelling evidence for active HHV-6 replication. Whether this replication is a bystander and marker of immune dysregulation or has a pathogenic role in these dermatologic conditions remains undefined but merits further investigation. SJS is a serious and potentially lethal disease. There is currently no way to predict who may be affected and no means of prevention. Further research into the association of HHV-6 and SJS may illuminate its pathogenesis, help define the cascade of immunologic events induced by drug and viral antigens, and bring us closer to achieving enhanced prevention and treatment of this poorly understood disease. REFERENCES 1. Bastuji-Garin S, Rzany B, Stern RS, Shear NH, Naldi L, Roujeau JC Clinical classification of cases of toxic epidermal necrolysis, Stevens-Johnson syndrome, and erythema multiforme. Arch Dermatol  1993; 129: 92– 6. Google Scholar CrossRef Search ADS PubMed  2. Roujeau JC, Huynh TN, Bracq C, Guillaume JC, Revuz J, Touraine R Genetic susceptibility to toxic epidermal necrolysis. Arch Dermatol  1987; 123: 1171– 3. Google Scholar CrossRef Search ADS PubMed  3. 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TI - High-Level Human Herpesvirus-6 Viremia Associated With Onset of Stevens-Johnson Syndrome: Report of Two Cases
JF - Journal of Burn Care & Research
DO - 10.1097/BCR.0b013e3181d0f48b
DA - 2010-03-01
UR - https://www.deepdyve.com/lp/oxford-university-press/high-level-human-herpesvirus-6-viremia-associated-with-onset-of-RHmz2kpoUp
SP - 365
EP - 368
VL - 31
IS - 2
DP - DeepDyve
ER -