How to differentiate skin rash in covid, mononucleosis, chickenpox, sixth disease and measles.

PURPOSE OF REVIEW: Skin rashes seen during COVID-19 usually feature maculopapular or vesicular morphology, thus mimicking cutaneous eruptions occurring in other common infectious dermatoses, such as mononucleosis, chickenpox, sixth disease and measles, with possible diagnostic mistakes. In this review article, we sought to provide a practical overview about clinical appearance of skin rashes related to SARS-CoV-2 infection. RECENT FINDINGS: The study summarizes literature evidence on clinical patterns of COVID-19-associated maculopapular or vesicular rash, with a particular emphasis on the principal points of differentiation with possible mimickers. SUMMARY: Several differences do exist between rashes due to SARS-CoV-2 infection and other viral eruptions, mainly including lesions morphology, spreading pattern, symptoms and mucosal involvement. The increase of awareness of such features among clinicians may help promptly recognize COVID-19-related exanthemas in order to take proper action to manage the infection.

Clinical Features of Complex Febrile Seizure Caused by Primary Human Herpesvirus 6B Infection.

BACKGROUND: It is well known that febrile seizures are commonly occur in children with exanthem subitum. In this study, we compared the clinical features and backgrounds of patients with complex febrile seizures with and without primary human herpesvirus 6B infection. METHODS: Sixty-two patients were enrolled after experiencing their first febrile seizure. Primary human herpesvirus 6B infection was confirmed when human herpesvirus 6B DNA was detected and human herpesvirus 6B antibody was negative in serum obtained during the acute phase of infection. Patient age, gender, and features of seizures were evaluated between patients with and without human herpesvirus 6B infection. RESULTS: Thirty patients with complex febrile seizure were diagnosed with primary human herpesvirus 6B infection. Those with primary human herpesvirus 6B infection (median, 13 months; range, seven to 39 months) were significantly younger than those without primary human herpesvirus 6B infection (median, 19 months; range, 10 to 59 months) (P = 0.001), and the proportion of males was significantly higher in patients without primary human herpesvirus 6B infection (male/female, 25/7) than in those with the infection (male/female, 14/16) (P = 0.017). An interval between fever onset and seizures of more than 24 hours was significantly more common in patients with primary human herpesvirus 6B infection (15 of the 30 patients) than in those without primary HHV-6B infection (two of 32 patients) (P < 0.001). CONCLUSIONS: A younger age at onset, a different gender ratio compared with febrile seizure due to other causes, and the length of interval between fever and seizures were features of complex febrile seizure associated human herpesvirus 6B infection. These findings may suggest a mechanism of complex febrile seizure onset different from that due to other causes.

Comparison of initial and final diagnoses in children with acute febrile illness: A retrospective, descriptive study: Initial and final diagnoses in children with acute fever.

BACKGROUND: This study aimed to elucidate the etiologies and diagnostic errors of early-phase pediatric fever without an obvious cause. METHODS: This single-center, retrospective, descriptive study included 1334 febrile children hospitalized at Beppu Medical Center in Japan between 2014 and 2018. Eligibility criteria were age ≤12 years, axillary temperature ≥38.0°C, and fever duration ≤7 days at admission. Initial diagnoses on the day of admission and final diagnoses at defervescence were divided into initial fever with identified source (FIS) and initial fever without source (FWS) and final FIS and final FWS, respectively. The etiology of initial FWS and diagnostic discordance between initial FIS and final FIS were investigated. RESULTS: Of the 1334 participants, 94 (7.0%) were diagnosed with initial FWS. Among patients with initial FWS, final diagnoses were confirmed in 40 (43%), including Kawasaki disease in 17, urinary tract infection in 5, bacteremia in 4, exanthem subitum in 3, and the others in 11. Among the 1275 patients diagnosed with final FIS, diagnostic discordances between initial and final diagnoses were observed in 131 patients (10%). The multiple logistic regression analysis identified increased serum C-reactive protein value at admission (odds ratio [OR]: 1.09; 95% confidence interval [CI]: 1.06-1.13), exanthem subitum (OR: 409; 95% CI: 119-1399), and Kawasaki disease (OR: 14.3; 95% CI: 8.7-23.3) as independent risk factors for diagnostic discordance. CONCLUSION: Exanthem subitum and Kawasaki disease may be undiagnosed or misdiagnosed in febrile children with fever duration ≤7 days.

Leukocytoclastic Vasculitis Associated with HHV6-A/ciHHV6-A and HHV6-B Coinfection in an Immunocompetent Woman.

BACKGROUND AND OBJECTIVE: Leukocytoclastic vasculitis (LCV) is a small vessel vasculitis that can be limited to the skin but may also affect other organs. Often, its cause is unknown. LCV has previously been reported to occur with the reactivation of human herpesvirus 6 (HHV-6). Here, we report a second instance of HHV-6 reactivation in a 43-year-old woman with idiopathic cutaneous LCV. CASE DESCRIPTION: In this case, the patient was immunocompetent, and testing revealed that she had inherited chromosomally integrated human herpesvirus 6 variant A (iciHHV6-A) with a parallel skin infection of HHV-6B. The integrated ciHHV-6A strain was found to be transcriptionally active in the blood, while HHV-6B late antigen was detected in a skin biopsy. The patient's rash was not accompanied by fever nor systemic symptoms and resolved over four weeks without any therapeutic intervention. CONCLUSION: In light of the transcriptional activity documented in our case, further examination of a possible role for HHV-6 in the etiology of LCV is warranted.

Children infected by human herpesvirus 6B with febrile seizures are more likely to develop febrile status epilepticus: A case-control study in a referral hospital in Zambia.

BACKGROUND: Human herpesvirus 6B (HHV-6B) is the causative agent of Roseola infantum, and has also been suggested to play a role in the pathogenesis of febrile seizures in young children, a percentage of whom go on to develop febrile status epilepticus (FSE), but the existing data is conflicting and inconclusive. HHV-6A is a distinct species, rarely detected in most parts of the world, but prior studies suggest a higher prevalence in febrile African children. We describe a case-control study comparing the frequency of HHV-6A and/or HHV-6B infections in children with febrile seizures (including FSE) and a control group of febrile children without seizures. METHODS: We recruited children aged 6 to 60 months admitted with a febrile illness with (cases) or without (controls) seizures presenting within 48 hours of commencement of fever. Three milliliters of whole blood was centrifuged and plasma stored at -80°C for pooled screening for HHV-6B and HHV-6A by Taqman real-time polymerase chain reaction. RESULTS: 102 cases and 95 controls were recruited. The prevalence of HHV-6B DNA detection did not differ significantly between cases (5.8% (6/102)) and controls (10.5% (10/95)) but HHV-6B infection was associated with FSE (OR, 15; 95% CI, [1.99-120]; P= 0.009). HHV-6A was not detected. CONCLUSION: Prevalence of HHV-6B was similar among cases and controls. Within the FS group, HHV-6B infection was associated with FSE, suggesting HHV-6B infections could play a role in the pathogenesis of FSE.

Encefalopatía por virus herpes 6 como complicación de exantema súbito / Encephalopathy due to human herpesvirus 6 infection as exanthema subitum complication

La principal manifestación clínica del herpesvirus 6 es el exantema súbito (también conocido como roséola o sexta enfermedad) y el síndrome febril. Las manifestaciones en el sistema nervioso central no son infrecuentes en la infección por herpesvirus 6, y su fisiopatología no está esclarecida, pero precisan diagnóstico y tratamiento temprano para evitar secuelas potencialmente graves. Se presenta el caso de una niña inmunocompetente de 2 años con cuadro de encefalitis como complicación de infección por herpesvirus 6. Se destaca la importancia del diagnóstico oportuno a fin de instaurar un adecuado tratamiento y seguimiento para evitar complicaciones secundarias a la afectación del sistema nervioso central.

The main clinical manifestation of human herpesvirus 6 is exanthema subitum (also known as roseola infantum) and febrile syndrome. Central nervous system manifestations are not unusual in herpesvirus 6 infection, and even though the pathophysiology is not clear, they need to be early diagnosed and treated in order to avoid potentially serious damage. We present the case of an immunocompetent 2-year-old girl with encephalitis as a complication of herpesvirus 6 infection. We want to emphasize the significance of an early diagnosis and treatment in order to prevent further complications due to the central nervous system extension.

[Encephalopathy due to human herpesvirus 6 infection as exanthema subitum complication]. / Encefalopatía por virus herpes 6 como complicación de exantema súbito.

The main clinical manifestation of human herpesvirus 6 is exanthema subitum (also known as roseola infantum) and febrile syndrome. Central nervous system manifestations are not unusual in herpesvirus 6 infection, and even though the pathophysiology is not clear, they need to be early diagnosed and treated in order to avoid potentially serious damage. We present the case of an immunocompetent 2-year-old girl with encephalitis as a complication of herpesvirus 6 infection. We want to emphasize the significance of an early diagnosis and treatment in order to prevent further complications due to the central nervous system extension.

La principal manifestación clínica del herpesvirus 6 es el exantema súbito (también conocido como roséola o sexta enfermedad) y el síndrome febril. Las manifestaciones en el sistema nervioso central no son infrecuentes en la infección por herpesvirus 6, y su fisiopatología no está esclarecida, pero precisan diagnóstico y tratamiento temprano para evitar secuelas potencialmente graves. Se presenta el caso de una niña inmunocompetente de 2 años con cuadro de encefalitis como complicación de infección por herpesvirus 6. Se destaca la importancia del diagnóstico oportuno a fin de instaurar un adecuado tratamiento y seguimiento para evitar complicaciones secundarias a la afectación del sistema nervioso central.

Serum levels of matrix metalloproteinase-9 and tissue inhibitor of metalloproteinases-1 in human herpesvirus-6-infected infants with or without febrile seizures.

Human herpesvirus-6 (HHV-6) is a cause of exanthema subitum and, sometimes, of febrile seizures. However, the pathogenesis of febrile seizures associated with HHV-6 infection remains unclear. We investigated serum matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of metalloproteinases-1 (TIMP-1) levels in infants with HHV-6 infection. Serum levels of both MMP-9 and TIMP-1 were significantly higher in infants with HHV-6 infection than in controls. Serum TIMP-1 levels were significantly higher in infants with febrile seizures than in infants without febrile seizures. Serum MMP-9/TIMP-1 ratios were significantly lower in infants with febrile seizures than in infants without febrile seizures. In infants with HHV-6 infection, positive correlations were found between serum MMP-9 concentrations and the white blood cells (WBC) count, and between serum TIMP-1 concentrations and the WBC count. Positive correlations were also found between the amounts of HHV-6 DNA and the ratios of MMP-9/TIMP-1 in infants with HHV-6 infection. In conclusion, we suggest that high serum levels of MMP-9 and TIMP-1 in infants with HHV-6 infection may induce dysfunction of the blood-brain barrier, eventually causing febrile seizures.

Simultaneous presence of human herpesvirus 6 and adenovirus infections in intestinal intussusception of young children.

AIM: This prospective study investigated the role of viral infections in the pathogenesis of intussusception, including human herpesvirus 6 (HHV-6), a known lymphotropic virus. METHODS: Fifty-three children with intussusception treated in hospital were enroled, and children of comparable age and gender served as controls. Blood, stool and throat swab specimens, as well as mesenteric lymph nodes and pieces of intestine from patients requiring surgery were tested for various viruses by PCR methods. RESULTS: Altogether, 85% of intussusception cases showed evidence of a recent or ongoing viral infection. Among the 53 intussusception cases, adenovirus was detected in 25 (47%), HHV-6 in 24 (45%), rhinovirus in 12 (23%), cytomegalovirus in 7 (13%), enterovirus in 4 (8%) and rotavirus in 3 (6%) patients. Of the 50 whole blood samples, 44% were positive for HHV-6 and of the 16 resected mesenteric lymph nodes, 50% were positive for HHV-6. Simultaneous presence of HHV-6 and adenovirus infection correlated significantly with intussusception (OR 12.1, 95% CI 2.2 to 66.5). CONCLUSIONS: A statistically significant association was observed between adenovirus and childhood intussusception. HHV-6 was a common finding and occurred concomitantly with other viruses. A simultaneous infection with HHV-6 and adenovirus carried the highest risk for intussusception.

[Lymphohistiocytic activation syndrome and Burkholderia cepacia complex infection in a child revealing chronic granulomatous disease and chromosomal integration of the HHV-6 genome]. / Syndrome d'activation lymphohistiocytaire associé à une infection àBurkholderia cepacia complex chez un nourrisson révélant une granulomatose septique et une intégration génomique du virus HHV-6.

Chronic granulomatous disease (GCD) is characterized by severe infections, notably with Burkholderia cepacia complex (BCC). GCD is rarely complicated by lymphohistiocytic activation syndromes, most often secondary to bacterial or viral infections, in particular human herpes virus 6 (HHV-6). We describe the case of a 10-month-old boy who suffered from multiple organ failure due to a BCC infection and a lymphohistiocytic activation syndrome, leading to diagnosis of GCD. The initial search for HHV-6 was positive and the infection was treated, but the progression and viral sample analysis led to the chromosomal integration of the HHV-6 genome. The child's clinical condition was normal after bone marrow transplantation. This case describes a rare association between GCD and lymphohistiocytic activation syndrome and raises questions about the role played by chromosomal integration of the HHV-6 genome.

[Sulfasalazine-induced hypersensitivity syndrome associated with human herpesvirus 6 reactivation and induction of antiphospholipid syndrome]. / Síndrome de hipersensibilidad inducido por sulfasalazina asociado a reactivación de VHH-6 e inducción de síndrome antifosfolípido.

Drug-induced hypersensitivity syndrome is a toxicoderma with systemic involvement. Suspicion of this disorder obliges rapid withdrawal of the suspected drug, which may have been introduced up to 3 months earlier. Screening for human herpesvirus (HHV) 6 reactivation is important both for its diagnostic value and for its association with a poor prognosis. Reactivation of this virus is not a contraindication for systemic corticosteroid treatment, which should be tapered slowly in order to avoid recurrence. The possible appearance of antiphospholipid antibodies must also be considered in those cases associated with thrombocytopenia, altered hemostasis, or thrombotic events. Autoimmune disorders may also develop as a sequela of the condition. Medium-to-long-term follow-up is required even after complete resolution of the condition. We describe a new case of sulfasalazine-induced hypersensitivity syndrome associated with HHV-6 reactivation and the induction of anticardiolipin and anti-thyroid peroxidase antibodies.

A case of drug-induced hypersensitivity syndrome-like symptoms following HHV-6 encephalopathy.

BACKGROUND: Drug-induced hypersensitivity syndrome (DIHS) is a rare but severe disorder due to a systemic hypersensitivity reaction. We report on a case with DIHS-like symptoms following human herpes virus 6 (HHV-6) infection complicated with encephalopathy. CASE SUMMARY: An 11-month-old girl suffered from a human herpes virus 6 (HHV-6) infection (exanthema subitum) complicated with encephalopathy. We treated the patient with continuous infusion of thiopental, assisted mechanical ventilation, methylprednisolone pulse therapy, and gamma-globulin infusion therapy starting on the fifth day of the illness and started phenobarbital administration on the eleventh day. The patient developed a fever, systemic erythematous exanthema, lymphadenopathy, and eosinophilia two weeks after the start of phenobarbital administration. Steroid therapy, methylprednisolone (4 mg/kg/day) followed by oral prednisolone (1 mg/kg/day), was started on the 28th day and was tapered off on the 72nd day after admission. Serum anti-HHV-6 IgG antibody elevation and the presence of HHV-6 DNA in the peripheral blood detected by polymerase chain reaction (PCR) analysis suggested reactivation of HHV-6 after the primary infection of HHV-6. Lymphocyte transformation test for phenobarbital was positive three weeks after the DIHS crisis. DISCUSSION: HHV-6 reactivation is a unique feature in DIHS. In general one develops DIHS accompanied by reactivation of HHV-6 which has been residing in the body since the initial infection (exanthema subitum) in early childhood. This is the first report of a patient with DIHS-like symptoms which developed immediately following the primary infection of HHV-6.

Exanthem subitum-associated encephalitis: nationwide survey in Japan.

We sought to clarify clinical features of exanthem subitum associated-encephalitis/encephalopathy, generally caused by primary human herpesvirus-6 infection in Japan. A two-part questionnaire was sent to hospitals between January 2003-December 2004. Of 3357 questionnaires, 2357 (70.2%) were returned, and 2293 (68.3%) were eligible for analysis. Eighty-six cases of exanthem subitum-associated encephalitis/encephalopathy were reported. Seventy-seven (89.5%) of 86 patients were diagnosed with human herpesvirus-6 infection by virologic examination. Although 41 (50.6%) of 81 patients had no sequelae, 38 (46.9%) had neurologic sequelae. Moreover, two fatal cases (2.5%) were reported. Pleocytosis was evident in only 4 (7.5%) of 53 patients, and cerebrospinal fluid protein levels were within normal range (23.4 +/- 14.6 mg/dL S.D.) in all patients. Human herpesvirus-6 DNA was detected in 21 (53.8%) of 39 patients. Abnormal computed tomography findings were a predictor of neurologic sequelae (P = 0.0097). As a consequence of this survey, we estimate that 61.9 cases of exanthem subitum-associated encephalitis occur every year. The disease prognosis was unexpectedly poor.

Bulging fontanelle in febrile infants: is lumbar puncture mandatory?

OBJECTIVE: To determine the aetiologies and clinical characteristics of infants with fever and a bulging fontanelle. DESIGN: The medical records of all febrile infants with a bulging fontanelle who underwent a lumbar puncture from January 2000 to February 2008 in Assaf Harofeh Medical Center, a university affiliated hospital in central Israel, were identified. RESULTS: 153 patients met the inclusion criteria. The male to female ratio was 100:53; age range was 3-11 months with a mean age of 5.6 (SD 1.8) months and a median age of 5 months. Cerebrospinal fluid pleocytosis was found in 42 cases (27.3%), including one case of bacterial meningitis (0.6%). Other leading diagnoses were aseptic meningitis (26.7%), upper respiratory tract infection (18.3%), viral disease not otherwise specified (15.6%), roseola infantum (8.5%) and acute otitis media (6.5%). Appearance on admission was described as good to excellent in 113 (73.8%) infants, none of whom had bacterial meningitis. 32 had aseptic meningitis and 17 had other bacterial disease (pneumonia, acute otitis media, pyelonephritis, bacteraemia, shigella or salmonella gastroenteritis). All the latter had, upon admission, symptoms, signs, laboratory tests or imaging studies suggesting a bacterial aetiology. CONCLUSIONS: In this large cohort, all infants who appeared well on admission and had normal clinical, laboratory and imaging studies had benign (non-bacterial) disease. In an infant who appears well and has no evidence of bacterial disease, it is reasonable to observe the infant and withhold lumbar puncture. Prospective studies should be carried out to confirm this approach.

Predominant human herpesvirus 6 variant A infant infections in an HIV-1 endemic region of Sub-Saharan Africa.

Human herpesvirus 6, HHV-6, commonly infects children, causing febrile illness and can cause more severe pathology, especially in an immune compromised setting. There are virulence distinctions between variants HHV-6A and B, with evidence for increased severity and neurotropism for HHV-6A. While HHV-6B is the predominant infant infection in USA, Europe and Japan, HHV-6A appears rare. Here HHV-6 prevalence, loads and variant genotypes, in asymptomatic compared to symptomatic infants were investigated from an African region with endemic HIV-1/AIDS. DNA was extracted from blood or sera from asymptomatic infants at 6 and 18 months age in a population-based micronutrient study, and from symptomatic infants hospitalised for febrile disease. DNA was screened by qualitative and quantitative real-time PCR, then genotyped by sequencing at variable loci, U46 (gN) and U47 (gO). HIV-1 serostatus of infants and mothers were also determined. HHV-6 DNA prevalence rose from 15% to 22% (80/371) by 18 months. At 6 months, infants born to HIV-1 positive mothers had lower HHV-6 prevalence (11%, 6/53), but higher HCMV prevalence (25%, 17/67). HHV-6 positive febrile hospitalized infants had higher HIV-1, 57% (4/7), compared to asymptomatic infants, 3% (2/74). HHV-6A was detected exclusively in 86% (48/56) of asymptomatic HHV-6 positive samples genotyped. Co-infections with both strain variants were linked with higher viral loads and found in 13% (7/56) asymptomatic infants and 43% (3/7) HIV-1 positive febrile infants. Overall, the results show HHV-6A as the predominant variant significantly associated with viremic infant-infections in this African population, distinct from other global cohorts, suggesting emergent infections elsewhere.

Papular-purpuric gloves and socks syndrome in children and adolescents.

We describe the case of a 12-year-old boy with gloves and socks syndrome caused by coinfection with HHV-6 and PVB19, and review the published cases from 5 to 18 years of age to profile the disease in this age group. The review of the literature yielded 25 cases of gloves and socks syndrome. Most patients were febrile and had acute PVB19 infection.

Serum and cerebrospinal fluid levels of cytokines in acute encephalopathy associated with human herpesvirus-6 infection.

Human herpesvirus-6 (HHV-6) is a causative agent of exanthema subitum. The immunological pathogenesis of acute encephalopathy associated with HHV-6 infection is still unclear. We measured the concentrations of interferon-gamma (IFN-gamma), tumor necrosis factor-alpha (TNF-alpha), interleukin-2 (IL-2), IL-4, IL-6, IL-10, and soluble TNF receptor 1 (sTNFR1) in serum and cerebrospinal fluid (CSF) during the acute stage in 15 infants with acute encephalopathy and 12 with febrile seizures associated with HHV-6 infection. The serum IL-6, IL-10, sTNFR1, CSF IL-6, and sTNFR1 levels of infants with encephalopathy who had neurological sequelae (n=9) were significantly higher than those with febrile seizures (p=0.011, 0.043, 0.002, 0.029, and 0.005, respectively). In acute encephalopathy, serum IL-6, sTNFR1, and CSF IL-6 levels in infants with neurological sequelae were significantly higher than those without (n=6) neurological sequelae (p=0.043, 0.026, and 0.029, respectively), and serum IFN-gamma, IL-6, IL-10, and sTNFR1 levels were significantly higher than those in the CSF (p=0.037, 0.037, 0.001, and 0.021, respectively). There were no significant differences in serum or CSF cytokine levels between infants who were positive for HHV-6 DNA in the CSF (n=6) compared to those who were negative (n=9). We suggest that cytokines mediate the pathogenesis of acute encephalopathy associated with HHV-6 infection, and that the elevated levels of serum IL-6, sTNFR1, and CSF IL-6 are important for predicting neurological sequelae.

Carbamazepine-induced DRESS and HHV6 primary infection: the importance of skin tests.

SUMMARY: A 34-year-old male with a 20-year history of epilepsy was treated with valproic acid and phenobarbital. As he had frequent convulsive fits, carbamazepine (CBZ) was added. Thirty-four days later, the patient developed hyperthermia, (39.5 degrees C), cervical lymphadenopathy and generalized cutaneous exfoliated maculae and papulae. Biochemical investigation was characterized by a white cell count of 16.1 x 103/microl (17% eosinophils) and increased levels of aspartate aminotransferase and alanine aminotransferase (50 and 116 IU/L, respectively). HHV6 serological tests performed on day 21, detected anti HHV6 IgM, suggesting a HHV6 primary infection. Hence, CBZ was discontinued. One month later, the skin eruption, fever, lymph node swelling, liver dysfunction, and eosinophilia were progressively relieved. Six weeks after complete recovery, prick and patch skin tests were performed. They were strongly positive at 48-h reading. This report suggests the usefulness of skin tests in diagnosing CBZ-induced-DRESS, as well as s possible association between DRESS and HHV6 primary infection.

Association of human herpesvirus 6 reactivation with the flaring and severity of drug-induced hypersensitivity syndrome.

BACKGROUND: Drug-induced hypersensitivity syndrome (DIHS) is an adverse reaction with clinical signs of fever, rash and internal organ involvement. In the vast majority of patients in Japan, the causative drugs for DIHS are limited to the following eight: carbamazepine, phenytoin, phenobarbital, zonisamide, mexiletine, dapsone, salazosulfapyridine and allopurinol. The association of human herpesvirus (HHV)-6 reactivation with DIHS has been reported by various groups. OBJECTIVES: To confirm the relationship between the flaring and severity of DIHS and HHV-6 reactivation. METHODS: We evaluated 100 patients with drug rash and systemic symptom(s) caused by the drugs associated with DIHS. HHV-6 reactivation was examined by serological antibody assay and quantitative real-time polymerase chain reaction assay of serial serum samples. RESULTS: Anti-HHV-6 IgG titres increased in 62 of 100 patients, 14-28 days after the onset of symptoms. These patients suffered from severe organ involvement and a prolonged course compared with 38 patients showing no reactivation of HHV-6. Significant amounts of HHV-6 DNA were detected in serum samples from 18 of the 62 patients. Flaring of symptoms such as fever and hepatitis was closely related to HHV-6 reactivation in these 18 patients. It should be emphasized that all five patients with fatal outcome and 10 patients with renal failure were in the HHV-6 reactivation group. CONCLUSIONS: A combination of immunological reaction to a drug and HHV-6 reactivation results in the severe course of DIHS. The demonstration of HHV-6 reactivation is a useful marker of diagnosis as well as prognosis in DIHS.