SUMMARY: Chromosomally integrated human herpesvirus 6 (ciHHV‐6) is a condition in which the complete HHV‐6 genome is integrated into the host germ line genome and is vertically transmitted in a Mendelian manner. The condition is found in less than 1% of controls in the USA and UK, but has been found at a somewhat higher prevalence in transplant recipients and other patient populations in several small studies. HHV‐6 levels in whole blood that exceed 5.5 log10 copies/ml are strongly suggestive of ciHHV‐6. Monitoring DNA load in plasma and serum is unreliable, both for identifying and for monitoring subjects with ciHHV‐6 due to cell lysis and release of cellular DNA. High HHV‐6 DNA loads associated with ciHHV‐6 can lead to erroneous diagnosis of active infection. Transplant recipients with ciHHV‐6 may be at increased risk for bacterial infection and graft rejection. ciHHV‐6 can be induced to a state of active viral replication in vitro. It is not known whether ciHHV‐6 individuals are put at clinical risk by the use of drugs that have been associated with HHV‐6 reactivation in vivo or in vitro. Nonetheless, we urge careful observation when use of such drugs is indicated in individuals known to have ciHHV‐6. Little is known about whether individuals with ciHHV‐6 develop immune tolerance for viral proteins. Further research is needed to determine the role of ciHHV‐6 in disease. Copyright © 2011 John Wiley & Sons, Ltd.

Extranodal NK/T-cell lymphoma, nasal type, is a rare and highly aggressive disease with a grim prognosis. No therapeutic strategy is currently identified in relapsing patients. We report the results of a French prospective phase II trial of an L-asparaginase-containing regimen in 19 patients with relapsed or refractory disease treated in 13 centers. Eleven patients were in relapse and 8 patients were refractory to their first line of treatment. L-Asparaginase–based treatment yielded objective responses in 14 of the 18 evaluable patients after 3 cycles. Eleven patients entered complete remission (61%), and only 4 of them relapsed. The median overall survival time was 1 year, with a median response duration of 12 months. The main adverse events were hepatitis, cytopenia, and allergy. The absence of antiasparaginase antibodies and the disappearance of Epstein-Barr virus serum DNA were significantly associated with a better outcome. These data confirm the excellent activity of L-asparaginase–containing regimens in extranodal NK/T-cell lymphoma. L-Asparaginase–based treatment should thus be considered for salvage therapy, especially in patients with disseminated disease. First-line L-asparaginase combination therapy for extranodal NK/T-cell lymphoma warrants evaluation in prospective trials. This trial is registered at www.clinicaltrials.gov as #NCT00283985.

Drug reaction with eosinophilia and systemic symptoms (DRESS) is a severe, drug-induced reaction that involves both the skin and the viscera. Evidence for reactivation of herpes family viruses has been seen in some DRESS patients. To understand the immunological components of DRESS and their relationship to viral reactivation, we prospectively assessed 40 patients exhibiting DRESS in response to carbamazepine, allopurinol, or sulfamethoxazole. Peripheral blood T lymphocytes from the patients were evaluated for phenotype, cytokine secretion, and repertoire of CD4⁺ and CD8⁺ and for viral reactivation. We found Epstein-Barr virus (EBV), human herpes virus 6 (HHV-6), or HHV-7 reactivation in 76% of the patients. In all patients, circulating CD8⁺ T lymphocytes were activated, exhibited increased cutaneous homing markers, and secreted large amounts of tumor necrosis factor–α and interferon-γ. The production of these cytokines was particularly high in patients with the most severe visceral involvement. In addition, expanded populations of CD8⁺ T lymphocytes sharing the same T cell receptor repertoire were detected in the blood, skin, liver, and lungs of patients. Nearly half of these expanded blood CD8⁺ T lymphocytes specifically recognized one of several EBV epitopes. Finally, we found that the culprit drugs triggered the production of EBV in patients’ EBV-transformed B lymphocytes. Thus, cutaneous and visceral symptoms of DRESS are mediated by activated CD8⁺ T lymphocytes, which are largely directed against herpes viruses such as EBV.

Case Report from JAMA Dermatology — Twelve-Year Analysis of Severe Cases of Drug Reaction With Eosinophilia and Systemic Symptoms — A Cause of Unpredictable Multiorgan Failure

INFLUENZA EPIDEMICS have an important and well-documented impact on mortality, particularly in at-risk individuals, including elderly persons.^1-4 Recent work⁵ suggests that influenza epidemics are also associated with an elevated number of hospitalizations. On the other hand, their impact on uncomplicated morbidity and their consequences on health care utilization and lost productivity are still relatively unclear, despite the development of influenza surveillance systems in many countries. These systems are based on data collected from physicians who report cases of syndromes meeting a clinical case definition of influenza, sometimes but not always combined with virologic testing; they make it possible to detect epidemics early, to identify the circulating viral strains, and to supply quantitative information, for example, about the number of "excess" physician visits associated with an epidemic.^6,7 For several reasons, however, the results of this surveillance yield an incomplete picture of the true impact of epidemics. The clinical expression of the infection caused by influenza viruses is variable, and some physician visits for influenza infection will not be counted (and no sample will be taken) because the patient's clinical presentation does not meet the case definition. Carrat et al⁸ previously showed that nearly half of the patients visiting a physician for influenza had an attenuated form of the disease. Moreover, some individuals with influenza do not visit physicians; this fraction may represent 30% to 65% of patients whose clinical picture suggests influenza.^9,10 These individuals cannot be captured by a medically based surveillance system. At the other end of the spectrum, some patients may visit a physician several times for the same influenza episode,¹¹ and these new visits are rarely counted. Failure of the surveillance systems to take into account these categories of patients leads to a potentially important underestimation of the epidemic's impact on uncomplicated morbidity. This knowledge is nonetheless essential, especially for an accurate evalua tion of the clinical and economic benefits of preventive and treatment strategies against influenza.^12,13

Amoxicillin is known to induce exanthema in patients with EBV-induced infectious mononucleosis. It is widely recognized that the reactivation of herpesviruses, including HHV-6 (Human Herpesvirus 6) and EBV (Epstein Barr virus) is associated with DRESS (Drug Reaction with Eosinophilia and Systemic Symptoms). We report 7 cases of amoxicillin-induced flare in patients with DRESS induced by other drugs and investigate whether amoxicillin may have a direct effect on HHV-6 replication in vitro. 7 cases of DRESS with amoxicillin-induced flare were retrospectively analysed. The influence of amoxicillin on HHV-6 HST strain replication was studied in vitro in a human T lymphoblastoid MT4 cell line. The viral replication was quantified by immunofluorescence assay and by real-time polymerase chain reaction (PCR). Comparisons were performed using the Student's t test. Amoxicillin-induced flare was observed in 7 patients with DRESS induced by other drugs. In two cases HHV-6 reactivation was studied and was demonstrated by PCR. Amoxicillin neither modified cell viability nor cell proliferation for the range of tested concentrations. Amoxicillin increased the replication of HHV-6 at 25 microg*mL-1 and 50 microg*mL-1. Amoxicillin may induce a flare of DRESS, possibly by acting directly on herpesvirus replication.