Human Herpesvirus 6 (HHV-6) Infection

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Practice Essentials

Human herpesvirus 6 (HHV-6) is a herpesvirus that causes roseola infantum (or exanthema subitum [sixth disease]) in infants and children.[1] Infection is nearly ubiquitous by age 2 years.[2] Management of HHV-6 infection in immunocompetent hosts is supportive.

HHV-6 infection has been associated with complications of varying severity in hematopoietic stem cell transplant (HSCT) recipients, to a lesser degree in solid organ transplant (SOT) recipients, and in those who are otherwise immunosuppressed.[3] Owing to the complexities of testing, lack of strong evidence demonstrating causation of these complications, and the toxicities of potential therapies, the management of HHV-6 disease in immunosuppressed patients is controversial and not well understood.[2, 4] The exception to this is in immunocompromised patients with HHV-6 encephalitis, in whom the recommendation for treatment is strong.[5]

Background

HHV-6 was the sixth herpesvirus discovered, and infection in humans is nearly ubiquitous in the first two years of life, with seroprevalence rates surpassing 95% in most studies.[1, 3] HHV-6 was isolated in 1986 during attempts to find novel viruses in patients with lymphoproliferative diseases.

Infection is typically self-limited in children, but HHV-6 encephalitis can occur in immunocompromised patients and is the most feared complication of HHV-6 disease. This was first described in 1994.[5] HHV-6 encephalitis has been studied almost exclusively in HSCT and SOT recipients, in whom this clinical entity is most likely to occur.[4]

A beta herpesvirus (like cytomegalovirus [CMV], human herpesvirus 7 [HHV-7], and human herpesvirus 8 [HHV-8]), HHV-6 is characterized by two strains (A and B), considered distinct from each other.[4, 6] HHV-6B is the predominant strain of the virus documented in seroprevalence studies in the United States and Japan. HHV-6A disease has been documented to cause disease in only profoundly immunosuppressed hosts.[7] Whether the two strains have relevant clinical differences is not well understood, so, for the purposes of management, they are treated the same. For the remainder of this article, unless clinically relevant, HHV-6 will be used as a general term with the understanding that this largely refers to HHV6-B.

Primary HHV-6 infection usually occurs in infants or children and is a common cause of fever-induced seizures in children aged 6-24 months.[8] Acute HHV-6 infection is rare in immunocompetent adults but may manifest as a mononucleosislike illness characterized by fever, lymphadenopathy, and hepatitis.

Similar to other herpesviruses, HHV-6 infects a wide variety of cells and remains latent after initial infection.[6] Unlike other herpesviruses, HHV-6 has the ability to be chromosomally integrated, which, while occurring in less than 1% of the total population who newly acquire infection, is the suggested route of vertical transmission.[9, 10, 7] It is unclear what this means for the risk of both reactivation and/or disease causation. Only one case of reactivation of chromosomally integrated HHV-6A has been documented to cause HHV-6 encephalitis in an allogeneic HSCT recipient.[4, 7]

It is estimated that 1%-2% of the general population has chromosomally integrated HHV-6 (ciHHV-6) inherited from their parents.[4, 6] Chromosomally integrated HHV-6 has the potential to further complicate a clinician’s ability to interpret laboratory testing, particularly when attempting to diagnose HHV-6 encephalitis. In these patients, because ciHHV-6 DNA is present in all leukocytes, detection in whole-blood polymerase chain reaction (PCR) is virtually guaranteed. More specifically, in patients with encephalitis who have CSF leukocytosis, detection of HHV-6 DNA via PCR (provided the method is sensitive enough) will always occur, complicating differentiation of true disease from ciHHV6 DNA detected in white blood cells of the CSF. The challenges of ciHHV-6 also can confound the significance of viremia detection in other patients, such as those who are critically ill.[11] Methods to differentiate true infection from ciHHV-6 exist but are often not readily available clinically.[10]

HHV-6 encephalitis is the most well-described clinical entity in adults and occurs exclusively in the profoundly immunosuppressed population, particularly among HSCT or SOT recipients.[4, 5] Although this is the most feared complication of HHV-6 infection, it still remains relatively rare. In a 2019 retrospective review studying HSCT recipients of the Mayo Clinic, the reported incidence of HHV-6 encephalitis was 1.7% (9/531).[5] While the incidence was low, the mortality rate in these patients was 50%, and those who survived had high rates of persistent neurologic deficits.

A related argument over the role of HHV-6 in critically ill patients without baseline immunosuppression has also been detailed in the literature.[11] HHV-6 DNA can be measured in the serum of critically ill patients without symptoms of HHV-6 disease. Some studies have documented HHV-6 DNA detection in more than 25% of patients with septic shock. The significance of this finding is unclear. As with other herpesviruses (eg, CMV) that can reactivate and are believed to contribute to a worse prognosis in these patients, the association has not been shown to be causal (see Prognosis).

HHV-6 has also been associated with idiopathic pneumonitis and hepatitis.[4] In most cases in which an association with HHV-6 and other clinical entities (eg, multiple sclerosis, pityriasis rosea) has been described, there is not enough evidence to support pathophysiologic causation.[12, 13, 14, 15] Given their relative controversy and lack of strong evidence to support recommendations, they are not discussed further in this article.

In general, HHV-6 disease is most commonly associated with the following:

Laboratory diagnosis is rarely required in immunocompetent children presenting with classic roseola infantum; most often, HHV-6 infection is diagnosed based on its clinical features (see DDx and Workup). This is not the case in immunocompromised patients, in whom PCR of HHV-6 DNA is often used for workup.

No strongly recommended treatment for HHV-6 infection has been established, largely because the clinical relevance of HHV-6 isolation, except in cases of encephalitis, is not well understood. Treatment varies according to the presenting clinical situation and is usually unnecessary with primary infection in immunocompetent hosts. Supportive measures are the basis of care. Some infants may require hospitalization for atypical presentations or complications. Antivirals such as ganciclovir and foscarnet have been suggested as possible therapies for acute disease, but they remain controversial in most clinical settings aside from encephalitis. No vaccine exists. (See Treatment.)

For patient education resources, see the Bacterial and Viral Infections Center and the Children’s Health Center, as well as Mononucleosis and Skin Rashes in Children.

Pathophysiology

HHV-6 belongs to the Herpesviridae family and Betaherpesvirinae subfamily and to what is commonly referred to as the Roseolovirus genus.[17] Other viruses in the Herpesviridae family include CMV, herpes simplex virus (HSV)–1, HSV-2, Epstein-Barr virus (EBV), HHV-7, and HHV-8. HHV-6 can be subdivided into two strains: A and B.[18] While some studies have suggested that HHV-6A has a stronger affinity for CNS infection, this has not been demonstrated conclusively, and, for all practical purposes, HHV-6B is the strain that predominantly causes disease. Approximately 90% of the amino acids coded by their DNA are equivalent.[2]

The virion particle has the typical structure of a herpesvirus, with a central core containing the viral DNA, a capsid, and a tegument layer that is surrounded by a membrane. The cell surface marker CD46, which is broadly expressed throughout human nucleated cells, is used as a receptor for entry.

The exact mode by which HHV-6 is transmitted has yet to be fully elucidated. Studies indicate that primary HHV-6B infection is typically acquired during the first 24 months of life, with the peak of infection occurring at age 6-9 months. Vertical transmission of HHV-6 in children of parents who have chromosomally integrated HHV-6 viral DNA occurs in 1%-2% of births.[9, 10, 7]

The development of latent HHV-6 infection is a critical part of the pathophysiology. Like other latent herpes virus infections, latent HHV-6 is distributed among peripheral blood mononuclear cells (PBMCs), where it resides without active production of viral particles or viral proteins. In contrast to other herpesviruses that exist as extrachromosomal episomes (independent nonessential groups of DNA), the HHV-6 virus is integrated into host cell chromosomal DNA via covalent linkage. This has important implications for vertical transmission. Latency and asymptomatic shedding, predominantly in oral secretions, is believed to be the predominant route of transmission.[8] Latency is important, particularly when considering reactivation in immunosuppressed patients. For example, up to 45% of HSCT recipients will experience HHV-6 reactivation in the first few weeks after transplant, and rates among cord blood recipients are even higher (up to 90%). Note that reactivation (eg, detection of HHV-6 viral DNA in serum or CSF) is not the same clinical entity as active disease.[19, 4, 20, 21]

HHV-6 is the only human herpesvirus with the potential to integrate itself into the telomeric portion of its host’s chromosomes and thus can be transmitted vertically. Whether this has significant clinical implications is not well understood. One case report described an infant with X-linked severe combined immunodeficiency who reactivated chromosomally integrated HHV-6A.[7] The infection was shown via elegant work involving PCR of viral messenger RNA and fluorescent in-situ hybridization from both the boy’s mother and father’s genomics to have arisen from vertical acquisition.[7]

Theoretical links between HHV-6 infection and other clinical entities such as pityriasis rosea, multiple sclerosis, and even chronic fatigue syndrome have been described in the literature; however, these are either not strong associations or not well understood. Mechanisms for the pathophysiology of these associations have been suggested, although these discussions remain controversial owing to limited data, and the arguments are beyond the scope of this article.[22]

Etiology

HHV-6 disease can largely be thought of in two categories: (1) a disease of childhood that affects nearly the entire population and (2) a disease of reactivation in profoundly immunosuppressed individuals.[18] HHV-6 has also been associated with other clinical entities, although causality has not necessarily been proven, and their discussion is beyond the scope of this article (see Pathophysiology).

HHV-6 is the virus that most commonly causes the childhood disease roseola infantum.[1] It includes two genetically distinct strains: HHV-6A and HHV-6B. These two strains were originally considered variants of a single species, but genetic work has argued convincingly that they are different strains. Ultimately, the clinically relevant differences between HHV-6A and HHV-6B, such as ability to reactivate, tissue and cellular tropism, and geographic distribution, are not well understood.

HHV-6 infection in infants and children is associated with febrile seizures. In a landmark prospective study published in the New England Journal of Medicine, infants and children younger than 3 years were enrolled to try to elucidate the natural history of this infection.[8] In this study, all 2,200-plus patients with HHV-6 infection had fever, and the infection was responsible for 20% of emergency department visits and one third of the febrile seizures that were evaluated in their emergency department.

A 2005 study described 277 children who were prospectively monitored for HHV-6 from birth until age 2 years. By age 24 months, 77% of the children developed primary HHV-6 infection as determined with weekly PCR testing. Among 81 patients with a well-documented acquisition timeline, 93% developed symptoms. None of the patients had seizures, and 23% developed roseola.[23]

Because of the ubiquitous nature of HHV-6, in addition to advances in therapies used to treat malignancies, an important subset of HHV-6 disease occurs in profoundly immunosuppressed patients, more specifically among stem cell transplant recipients, in whom most of the research on this virus has been conducted. HHV-6 reactivation after HSCT is well described, and approximately 40%-50% of recipients will experience reactivation within 2-3 weeks after transplant, with risk varying by transplant type (ie, cord blood transplantation is believed to confer a higher risk).[6, 4, 21] HHV-6 encephalitis is a known complication of HSCT, particularly allogeneic transplantation.

States of relative immunosuppression are also associated with HHV-6 viremia, but the significance is not well understood (see Prognosis).[11] Management strategies are difficult owing to a lack of well-designed in vivo studies (see Treatment).

Epidemiology

United States statistics

HHV-6 infection is ubiquitous. HHV-6B is the most common strain in the United States. Infection almost uniformly occurs before age two years. Seroprevalence studies have documented greater than 95% seropositivity in children younger than two years.[2] The most common clinical presentation of infection in children is fever and rash, or the so-called exanthema subitum, or roseola infantum. Other viral infections are among the differential diagnoses, however, and the diagnosis of HHV-6 infection is typically presumed without confirmation or diagnostic testing.

International statistics

HHV-6 has a worldwide distribution. In an initial assessment of an HIV-1–endemic region of sub-Saharan Africa, the predominant form in infant infections was found to be HHV-6A, although this was not found to be the case upon reassessment of a larger subset of that population several years later.[16, 24] In Europe and Japan, as in the United States, HHV-6B is the agent mainly responsible for infant infection.

Age-, sex-, and race-related demographics

HHV-6 infection most commonly occurs after maternal antibodies have waned, usually between ages 6 months and 3 years (average, 9 months).

Serologic studies demonstrate that HHV-6 infects approximately 90% of children by age 2 years.[23] A prospective study found that HHV-6 was acquired in infancy, was usually symptomatic, and often resulted in a medical evaluation. However, only a minority of these patients developed roseola or febrile seizures with primary HHV-6 infection. Older siblings and other care takers appeared to be a source of HHV-6 transmission.[2, 23]

Primary HHV-6 infection is rare in adults. However, reactivation can occur at any age in immunosuppressed individuals.

HHV-6 infection has no sexual predilection and may occur in people of all races.

Prognosis

HHV-6 infections that occur early in life and in immunocompetent hosts are typically uncomplicated and have a self-limited course. The prognosis of these infections is usually excellent.

While the risk of /HHV-6 reactivation (which more precisely refers to detection of HHV-6 DNA via PCR, typically in serum or CSF) is high after HSCT, the risk of complications of this reactivation is not well understood. Strategies to prognosticate risk, including monitoring HHV-6 viral DNA in the serum of patients undergoing HSCT, varies by institution and cannot be strongly recommended, if at all, based on lack of evidence.[25, 26, 27]

The risk of HHV-6 encephalitis among HSCT recipients is associated with higher plasma viral loads (>105 copies/mL) and cord blood transplantation.[4, 5] HHV-6 encephalitis is associated with worse outcomes in immunosuppressed individuals. A 2019 review of patients with HHV-6 encephalitis after HSCT, while reporting low overall rates of encephalitis, reported high rates of persistent complications after disease. Sixty percent had residual neurologic deficits, and half of the patients died.

Lastly, as with other latent herpesviruses, HHV-6 viremia has been well described in patients with septic shock who otherwise did not have risk factors for immunosuppression at baseline. Well-designed prospective observational studies of these critically ill patients have suggested that this is common (up to 26% in one cohort[11] ). While HHV-6 viremia alone has not been demonstrated to increase the risk of mortality, HHV-6 viremia in the presence of other herpesviruses (eg, CMV viremia) has been associated with an increased mortality risk. While this is difficult to quantify, in general, HHV-6 viremia can be regarded as an indicator of illness severity, particularly in patients with other concurrent viremic events.

History

Human herpesvirus 6 (HHV-6) infection can be asymptomatic. Symptomatic manifestations occur predominately after primary infection in infants and after either primary or reactivation disease in immunocompromised adults.

HHV-6 is a common cause of hospital visits in infants with fever. Some estimates suggest that 20% of HHV-6 infections manifest as roseola, which is characterized by fever for 3-5 days and followed by an erythematous maculopapular rash.[8, 23] The rash starts at the trunk and spreads centrifugally to the face and limbs. More commonly, the infection presents as an acute nonspecific febrile illness in a child younger than 2 years. HHV-6 infection may also manifest as a rash alone.

Symptoms reported in children may include the following:

Symptoms reported in adults may include the following:

Symptoms reported in immunocompromised hosts and transplant recipients may include the following:

Physical Examination

Physical findings of HHV-6 infection are those expected with the symptoms described (see History). Very few physical examination findings exist in children who are infected with HHV-6 until skin findings become apparent.

Findings in infants that may suggest HHV-6 infection include the following (see the images below):



View Image

Nine-month-old infant boy presented with one-day history of high-grade fever and irritability. In the emergency department, the patient underwent sept....



View Image

N-month-old infant boy presented with one-day history of high-grade fever and irritability. In the emergency department, the patient underwent septic ....

HHV-6 infection in adults can have a wide variety of manifestations, which may range from mild to severe. Findings in healthy adults may include the following:

Findings in immunocompromised individuals may include the following:

Approach Considerations

Workup in infants and children is often directed at causes of fever, rash, and or febrile seizures, depending on the clinical scenario.

Diagnosis in recipients of organ transplants or patients with immunodeficiency, encephalitis, or hepatitis is often made using a combination of PCR and antibody detection. This diagnosis can be very difficult because of the paucity of evidence concerning the clinical significance of HHV-6 detection in serum via PCR. Many questions have been raised by researchers, including the significance in the setting of chromosomally integrated HHV-6. Further studies will be needed to move from associative to causative arguments about HHV-6.

Testing for HHV-6 disease is complicated by multiple factors, not the least of which is that serum HHV-6 DNA levels do not necessarily correlate with disease burden at the tissue level. Guidelines for diagnosis of HHV-6 infection in allogeneic stem cell transplant recipients have been published and should be referenced for an approach to diagnosis.[27, 32, 4]

Other studies used in the diagnosis of HHV-6 infection include diagnostic imaging, bronchoscopy, and tissue biopsy.

Laboratory Studies

Testing for HHV-6 disease requires a careful assessment of the pretest probability of disease, clinical syndrome, and the host.

The complete blood count (CBC) may show leukopenia and varying degrees of cytopenia (thrombocytopenia or anemia), especially in the setting of transplantation. In active infection, a CBC with differential may show leukopenia with relative leukocytosis.

Electrolytes should be evaluated and renal function tests performed, especially when considering treatment for HHV-6 encephalitis. Liver function tests may reveal hepatitis or liver dysfunction.

Culture

Standard peripheral cell culture, which takes 5-21 days and is labor-intensive, and shell vial assay culture are available in research settings for isolation of HHV-6.[33]

Immunohistochemistry

Immunohistochemical stains are available for detecting HHV-6 in formalin-fixed paraffin-embedded tissues. Only cells with active infection, as opposed to latent infection, stain positively with these antibodies. Immunohistochemical staining can be performed on tissue and cytologic samples. Depending on the pathology laboratory processing the samples, this can usually be completed in 1-3 days.

Serology

Primary infection can be demonstrated by seroconversion from immunoglobulin G (IgG)-negative to IgG-positive or by the presence of immunoglobulin M (IgM) to HHV-6 and a four-fold rise in titers from baseline over 4-6 weeks. Interpretation of antibodies in older children and adults is difficult given high seroprevalence and cross-reactivity and should not be used for diagnosis.[23]

Polymerase chain reaction assay

Rapid diagnosis of HHV-6 primary infections or reactivations can be facilitated by using quantitative PCR assays.[34] Detection of co-infections with multiple herpesviruses can also be accomplished, with quantitative results enabling monitoring of virus load during antiviral therapy.

Neither qualitative nor quantitative PCR of plasma is sufficient to distinguish between active viral replication and chromosomal integration with HHV-6. A higher specificity may be obtained by using reverse transcriptase PCR (RT-PCR) for viral messenger RNA when evaluating samples for active HHV-6 replication.[33, 35] However, this type of testing is not often readily available clinically.

Radiography and Computed Tomography

Chest radiography or computed tomography (CT) of the chest should be performed in patients with respiratory symptoms. These may show evidence of pneumonitis or pneumonia.

Brain MRI can be helpful and should be considered in the workup of HHV-6 encephalitis.

Indications for these and other diagnostic procedures depend on the clinical presentation, especially in immunocompromised patients.

Other Studies

In patients with central nervous system (CNS) symptoms, lumbar puncture can be performed to rule out other etiologies. In cases of febrile seizures due to HHV-6 infection, the cerebrospinal fluid (CSF) may reveal a mild pleocytosis with elevated protein levels, but it is often noteworthy for a lack of inflammatory response.[28, 8, 2] CSF can be sent for HHV-6 PCR studies. A positive result may indicate active HHV-6 infection in the CNS.

Tissue biopsy is especially relevant in solid-organ or bone-marrow transplant recipients who have evidence of graft rejection and in immunocompromised patients with severe hepatitis or hepatic failure. Samples should be sent for immunohistochemical staining.

Approach Considerations

Treatment of human herpesvirus 6 (HHV-6) infection varies according to the clinical scenario. In infants with roseola infantum, treatment is supportive. Infants who present with other manifestations of HHV-6 infection (eg, febrile seizures or CNS involvement) should undergo workup and treatment appropriate for these complications; overall, about 13% of infants with acute HHV-6 infection require hospitalization.

There is no vaccine for HHV-6 infection, and none currently exists in development.

Supportive Care

Supportive therapy, including acetaminophen for fever and adequate hydration, is indicated in all patients with symptomatic HHV-6 infection.

Antiviral Therapy

Decisions regarding antiviral therapy should carefully weigh the clinical scenario with the degree of diagnostic certainty, likelihood of a response or benefit, and the risk of systemic therapeutics. In immunocompetent patients, no antiviral pharmacologic therapy is recommended.

In immunosuppressed hosts with HHV-6 encephalitis, antiviral therapy is recommended.[17, 4] Foscarnet, ganciclovir, and cidofovir are the three antivirals that have in vitro activity against HHV-6. Brincidofovir may offer an additional mode of therapy with less toxicity in the future, but this has not been studied. There are no in vivo or randomized controlled trials that provide supporting evidence for any of these therapies, and use of them in this clinical scenarios is considered off-label. Therapy is often limited by toxicities. Ganciclovir is associated with cytopenias and bone-marrow suppression. Foscarnet is associated with renal failure. Close monitoring of cell counts and renal function in the setting of antiviral therapy for HHV-6 disease is required.

Given the concern for HHV-6 encephalitis morbidity and mortality, elucidation of an effective pre-emptive strategy for prophylaxis with antivirals has been attempted several times. These have not been successful for two reasons. First, the dynamics of HHV-6 DNA levels in serum and its correlation to risk of encephalitis is not well understood. Second, the toxicities of prophylactic antivirals (eg, foscarnet and its risk for renal failure, ganciclovir and its risk for cytopenia) are unacceptably high in the transplant setting, in which they are typically considered for treatment. Ultimately, prophylaxis for HHV-6 infection in HSCT recipients is not recommended.

Medication Summary

Drug therapy specific to the infection is not currently a component of the standard of care for human herpesvirus 6 (HHV-6) infection. Supportive therapy, using antipyretics such as acetaminophen or ibuprofen, is indicated. Although HHV-6 is inhibited by several antiviral drugs (eg, ganciclovir and foscarnet) in the laboratory, no clinical trials have assessed their benefit, and their role in the treatment of HHV-6 infection remains to be determined.

Ganciclovir (Cytovene)

Clinical Context:  Ganciclovir is an acyclic nucleoside analogue of 2'-deoxyguanosine that inhibits replication of herpes viruses both in vitro and in vivo.

Foscarnet (Foscavir)

Clinical Context:  Foscarnet is an organic analogue of inorganic pyrophosphate that inhibits replication of known herpesviruses. It inhibits viral replication at pyrophosphate-binding sites on virus-specific DNA polymerases. Poor clinical response or persistent viral excretion during therapy may be due to viral resistance.

Class Summary

Nucleoside analogues are initially phosphorylated by viral thymidine kinase to eventually form a nucleoside triphosphate, resulting in the inhibition of viral replication.

Acetaminophen (Tylenol, FeverAll, Aspirin-Free Anacin Extra)

Clinical Context:  Acetaminophen is used as an antipyretic and analgesic. It reduces fever by acting directly on hypothalamic heat-regulating centers, thereby increasing dissipation of body heat via vasodilation and sweating.

Ibuprofen (Motrin, Advil, Ibu)

Clinical Context:  Ibuprofen is used as an antipyretic and analgesic. It inhibits inflammatory reactions, fever, and pain by decreasing prostaglandin synthesis. It is not recommended for children younger than 6 months.

Class Summary

Control of pain and fever is essential to quality patient care. Antipyretics inhibit central synthesis and release of prostaglandins that mediate the effect of endogenous pyrogens in the hypothalamus; thus, they promote the return of the set-point temperature to normal.

Nonsteroidal anti-inflammatory agents (NSAIDs) such as ibuprofen have analgesic, anti-inflammatory, and antipyretic activities. Their mechanism of action is unknown, but they may inhibit cyclooxygenase activity and prostaglandin synthesis. Other possible mechanisms include inhibition of leukotriene synthesis, lysosomal enzyme release, lipoxygenase activity, neutrophil aggregation, and various cell-membrane functions.

Author

John L Kiley, MD, Fellow, Department of Medicine, Infectious Disease Service, Brooke Army Medical Center/San Antonio Military Medical Center, San Antonio Uniformed Services Health Education Consortium; Assistant Professor of Clinical Medicine, Uniformed Services University of the Health Sciences

Disclosure: Nothing to disclose.

Coauthor(s)

Dana M Blyth, MD, Associate Professor, Department of Medicine, Uniformed Services University of the Health Sciences; Adjunct Assistant Professor, Department of Medicine, University of Texas Health Science Center at San Antonio School of Medicine; Staff Physician, Department of Medicine, Infectious Disease Service, Brooke Army Medical Center, San Antonio Military Medical Center, San Antonio Uniformed Services Health Education Consortium (SAUSHEC)

Disclosure: Nothing to disclose.

Chief Editor

Burke A Cunha, MD, Professor of Medicine, State University of New York School of Medicine at Stony Brook; Chief, Infectious Disease Division, Winthrop-University Hospital

Disclosure: Nothing to disclose.

Additional Contributors

Michelle R Salvaggio, MD, FACP, Assistant Professor, Department of Internal Medicine, Section of Infectious Diseases, University of Oklahoma College of Medicine; Medical Director of Infectious Diseases Institute, Director, Clinical Trials Unit, Director, Ryan White Programs, Department of Medicine, University of Oklahoma Health Sciences Center; Attending Physician, Infectious Diseases Consultation Service, Infectious Diseases Institute, OU Medical Center

Disclosure: Received honoraria from Merck for speaking and teaching.

Acknowledgements

Ruchir Agrawal, MD Chief, Allergy and Immunology, Aurora Sheboygan Clinic

Ruchir Agrawal, MD, is a member of the following medical societies: American Academy of Allergy Asthma and Immunology, American Academy of Pediatrics, American College of Allergy, Asthma and Immunology, and American Medical Association

Disclosure: Nothing to disclose.

David F Butler, MD Professor of Dermatology, Texas A&M University College of Medicine; Chair, Department of Dermatology, Director, Dermatology Residency Training Program, Scott and White Clinic, Northside Clinic

David F Butler, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American Medical Association, American Society for Dermatologic Surgery, American Society for MOHS Surgery, Association of Military Dermatologists, and Phi Beta Kappa

Disclosure: Nothing to disclose.

Franklin Flowers, MD Chief, Division of Dermatology, Professor, Department of Medicine and Otolaryngology, Affiliate Associate Professor of Pediatrics and Pathology, University of Florida College of Medicine

Franklin Flowers, MD, is a member of the following medical societies: American College of Mohs Micrographic Surgery and Cutaneous Oncology

Disclosure: Nothing to disclose.

Ronald A Greenfield, MD Professor, Department of Internal Medicine, University of Oklahoma College of Medicine

Ronald A Greenfield, MD is a member of the following medical societies: American College of Physicians, American Federation for Medical Research, American Society for Microbiology, Central Society for Clinical Research, Infectious Diseases Society of America, Medical Mycology Society of the Americas, Phi Beta Kappa, Southern Society for Clinical Investigation, and Southwestern Association of Clinical Microbiology

Disclosure: Pfizer Honoraria Speaking and teaching; Gilead Honoraria Speaking and teaching; Ortho McNeil Honoraria Speaking and teaching; Abbott Honoraria Speaking and teaching; Astellas Honoraria Speaking and teaching; Cubist Honoraria Speaking and teaching; Forest Pharmaceuticals Speaking and teaching

Cris Jagar, MD Staff Physician, Department of Psychiatry, Trinitas Regional Medical Center

Disclosure: Nothing to disclose.

William D James, MD Paul R Gross Professor of Dermatology, Vice-Chairman, Residency Program Director, Department of Dermatology, University of Pennsylvania School of Medicine

William D James, MD is a member of the following medical societies: American Academy of Dermatology and Society for Investigative Dermatology

Disclosure: Elsevier Royalty Other

Sue J Jue, MD Associate Professor, Department of Pediatrics, Section of Infectious Diseases, East Carolina University

Disclosure: Nothing to disclose.

Ewa Koziorynska, MD Assistant Professor of Neurology, Comprehensive Epilepsy Center, State University of New York Downstate Medical Center

Ewa Koziorynska, MD is a member of the following medical societies: Sigma Xi

Disclosure: Nothing to disclose.

Leonard R Krilov, MD Chief of Pediatric Infectious Diseases and International Adoption, Vice Chair, Department of Pediatrics, Professor of Pediatrics, Winthrop University Hospital

Leonard R Krilov, MD is a member of the following medical societies: American Academy of Pediatrics, American Pediatric Society, Infectious Diseases Society of America, Pediatric Infectious Diseases Society, and Society for Pediatric Research

Disclosure: Medimmune Grant/research funds Clinical trials; Medimmune Honoraria Speaking and teaching; Medimmune Consulting fee Consulting

Larry I Lutwick, MD Professor of Medicine, State University of New York Downstate Medical School; Director, Infectious Diseases, Veterans Affairs New York Harbor Health Care System, Brooklyn Campus

Larry I Lutwick, MD is a member of the following medical societies: American College of Physicians and Infectious Diseases Society of America

Disclosure: Nothing to disclose.

Thomas J Marrie, MD Dean of Faculty of Medicine, Dalhousie University Faculty of Medicine, Canada

Thomas J Marrie, MD is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians, American Society for Microbiology, Canadian Infectious Disease Society, and Royal College of Physicians and Surgeons of Canada

Disclosure: Nothing to disclose.

Jeffrey Meffert, MD Assistant Clinical Professor of Dermatology, University of Texas School of Medicine at San Antonio

Jeffrey Meffert, MD is a member of the following medical societies: American Academy of Dermatology, American Medical Association, Association of Military Dermatologists, and Texas Dermatological Society

Disclosure: Nothing to disclose.

Peter S Miele, MD Medical Officer, Division of Antiviral Products, US Food and Drug Administration

Peter S Miele, MD is a member of the following medical societies: American College of Physicians-American Society of Internal Medicine and Infectious Diseases Society of America

Disclosure: Nothing to disclose.

Robert A Schwartz, MD, MPH Professor and Head, Dermatology, Professor of Pathology, Pediatrics, Medicine, and Preventive Medicine and Community Health, University of Medicine and Dentistry of New Jersey-New Jersey Medical School

Robert A Schwartz, MD, MPH is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American College of Physicians, and Sigma Xi

Disclosure: Nothing to disclose.

Margo A Smith, MD Associate Program Director, Department of Medicine, Washington Hospital Center; Assistant Professor, Department of Internal Medicine, Section of Infectious Diseases, George Washington University

Margo A Smith, MD is a member of the following medical societies: American Society for Microbiology

Disclosure: Nothing to disclose.

Russell W Steele, MD Head, Division of Pediatric Infectious Diseases, Ochsner Children's Health Center; Clinical Professor, Department of Pediatrics, Tulane University School of Medicine

Russell W Steele, MD is a member of the following medical societies: American Academy of Pediatrics, American Association of Immunologists, American Pediatric Society, American Society for Microbiology, Infectious Diseases Society of America, Louisiana State Medical Society, Pediatric Infectious Diseases Society, Society for Pediatric Research, and Southern Medical Association

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

References

  1. Yamanishi K, Okuno T, Shiraki K, Takahashi M, Kondo T, Asano Y, et al. Identification of human herpesvirus-6 as a causal agent for exanthem subitum. Lancet. 1988 May 14. 1(8594):1065-7. [View Abstract]
  2. De Bolle L, Naesens L, De Clercq E. Update on human herpesvirus 6 biology, clinical features, and therapy. Clin Microbiol Rev. 2005 Jan. 18(1):217-45. [View Abstract]
  3. Agut H. Deciphering the clinical impact of acute human herpesvirus 6 (HHV-6) infections. J Clin Virol. 2011 Nov. 52 (3):164-71. [View Abstract]
  4. Ogata M, Fukuda T, Teshima T. Human herpesvirus-6 encephalitis after allogeneic hematopoietic cell transplantation: what we do and do not know. Bone Marrow Transplant. 2015 Aug. 50 (8):1030-6. [View Abstract]
  5. Fida M, Hamdi AM, Bryson A, Razonable RR, Abu Saleh O. Long-term Outcomes of Patients With Human Herpesvirus 6 Encephalitis. Open Forum Infect Dis. 2019 Jul. 6 (7):ofz269. [View Abstract]
  6. Pantry SN, Medveczky PG. Latency, Integration, and Reactivation of Human Herpesvirus-6. Viruses. 2017 Jul 24. 9 (7):[View Abstract]
  7. Endo A, Watanabe K, Ohye T, Suzuki K, Matsubara T, Shimizu N, et al. Molecular and virological evidence of viral activation from chromosomally integrated human herpesvirus 6A in a patient with X-linked severe combined immunodeficiency. Clin Infect Dis. 2014 Aug 15. 59 (4):545-8. [View Abstract]
  8. Hall CB, Long CE, Schnabel KC, Caserta MT, McIntyre KM, Costanzo MA, et al. Human herpesvirus-6 infection in children. A prospective study of complications and reactivation. N Engl J Med. 1994 Aug 18. 331 (7):432-8. [View Abstract]
  9. Pellett PE, Ablashi DV, Ambros PF, Agut H, Caserta MT, et al. Chromosomally integrated human herpesvirus 6: questions and answers. Rev Med Virol. 2012 May. 22(3):144-55. [View Abstract]
  10. Ward KN, Leong HN, Nacheva EP, Howard J, Atkinson CE, Davies NW, et al. Human herpesvirus 6 chromosomal integration in immunocompetent patients results in high levels of viral DNA in blood, sera, and hair follicles. J Clin Microbiol. 2006 Apr. 44(4):1571-4. [View Abstract]
  11. Ong DSY, Bonten MJM, Spitoni C, Verduyn Lunel FM, Frencken JF, Horn J, et al. Epidemiology of Multiple Herpes Viremia in Previously Immunocompetent Patients With Septic Shock. Clin Infect Dis. 2017 May 1. 64 (9):1204-1210. [View Abstract]
  12. Kempf W, Burg G. Pityriasis rosea--a virus-induced skin disease? An update. Arch Virol. 2000. 145 (8):1509-20. [View Abstract]
  13. Challoner PB, Smith KT, Parker JD, MacLeod DL, Coulter SN, et al. Plaque-associated expression of human herpesvirus 6 in multiple sclerosis. Proc Natl Acad Sci U S A. 1995 Aug 1. 92(16):7440-4. [View Abstract]
  14. Voumvourakis KI, Kitsos DK, Tsiodras S, Petrikkos G, Stamboulis E. Human herpesvirus 6 infection as a trigger of multiple sclerosis. Mayo Clin Proc. 2010 Nov. 85(11):1023-30. [View Abstract]
  15. Pormohammad A, Azimi T, Falah F, Faghihloo E. Relationship of human herpes virus 6 and multiple sclerosis: A systematic review and meta-analysis. J Cell Physiol. 2018 Apr. 233 (4):2850-2862. [View Abstract]
  16. Tembo J, Kabwe M, Chilukutu L, Chilufya M, Mwaanza N, Chabala C, et al. Prevalence and risk factors for betaherpesvirus DNAemia in children >3 weeks and Clin Infect Dis</i>. 2015 Feb 1. 60 (3):423-31. [View Abstract]
  17. Hill JA, Zerr DM. Roseoloviruses in transplant recipients: clinical consequences and prospects for treatment and prevention trials. Curr Opin Virol. 2014 Dec. 9:53-60. [View Abstract]
  18. Caserta MT, Mock DJ, Dewhurst S. Human herpesvirus 6. Clin Infect Dis. 2001 Sep 15. 33 (6):829-33. [View Abstract]
  19. Aoki J, Numata A, Yamamoto E, Fujii E, Tanaka M, Kanamori H. Impact of Human Herpesvirus-6 Reactivation on Outcomes of Allogeneic Hematopoietic Stem Cell Transplantation. Biol Blood Marrow Transplant. 2015 Nov. 21 (11):2017-22. [View Abstract]
  20. Ogata M, Satou T, Kawano R, Goto K, Ikewaki J, Kohno K, et al. Plasma HHV-6 viral load-guided preemptive therapy against HHV-6 encephalopathy after allogeneic stem cell transplantation: a prospective evaluation. Bone Marrow Transplant. 2008 Feb. 41 (3):279-85. [View Abstract]
  21. Linder KA, McDonald PJ, Kauffman CA, Revankar SG, Chandrasekar PH, Miceli MH. Infectious Complications After Umbilical Cord Blood Transplantation for Hematological Malignancy. Open Forum Infect Dis. 2019 Feb. 6 (2):ofz037. [View Abstract]
  22. Leibovitch EC, Jacobson S. Evidence linking HHV-6 with multiple sclerosis: an update. Curr Opin Virol. 2014 Dec. 9:127-33. [View Abstract]
  23. Zerr DM, Meier AS, Selke SS, Frenkel LM, Huang ML, Wald A, et al. A population-based study of primary human herpesvirus 6 infection. N Engl J Med. 2005 Feb 24. 352 (8):768-76. [View Abstract]
  24. Bates M, Monze M, Bima H, Kapambwe M, Clark D, Kasolo FC, et al. Predominant human herpesvirus 6 variant A infant infections in an HIV-1 endemic region of Sub-Saharan Africa. J Med Virol. 2009 May. 81(5):779-89. [View Abstract]
  25. Galarraga MC, Gomez E, de Oña M, Rodriguez A, Laures A, Boga JA, et al. Influence of ganciclovir prophylaxis on citomegalovirus, human herpesvirus 6, and human herpesvirus 7 viremia in renal transplant recipients. Transplant Proc. 2005 Jun. 37(5):2124-6. [View Abstract]
  26. Ishiyama K, Katagiri T, Hoshino T, Yoshida T, Yamaguchi M, Nakao S. Preemptive therapy of human herpesvirus-6 encephalitis with foscarnet sodium for high-risk patients after hematopoietic SCT. Bone Marrow Transplant. 2011 Jun. 46 (6):863-9. [View Abstract]
  27. Pellett Madan R, Hand J, AST Infectious Diseases Community of Practice. Human herpesvirus 6, 7, and 8 in solid organ transplantation: Guidelines from the American Society of Transplantation Infectious Diseases Community of Practice. Clin Transplant. 2019 Mar 7. e13518. [View Abstract]
  28. Laina I, Syriopoulou VP, Daikos GL, Roma ES, Papageorgiou F, Kakourou T, et al. Febrile seizures and primary human herpesvirus 6 infection. Pediatr Neurol. 2010 Jan. 42(1):28-31. [View Abstract]
  29. Yao K, Honarmand S, Espinosa A, Akhyani N, Glaser C, Jacobson S. Detection of human herpesvirus-6 in cerebrospinal fluid of patients with encephalitis. Ann Neurol. 2009 Mar. 65(3):257-67. [View Abstract]
  30. Mori T, Mihara A, Yamazaki R, Shimizu T, Aisa Y, Suzuki S, et al. Myelitis associated with human herpes virus 6 (HHV-6) after allogeneic cord blood transplantation. Scand J Infect Dis. 2007. 39(3):276-8. [View Abstract]
  31. Gentile I, Talamo M, Borgia G. 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. BMC Infect Dis. 2010 Mar 6. 10:49. [View Abstract]
  32. Betts BC, Young JA, Ustun C, Cao Q, Weisdorf DJ. Human herpesvirus 6 infection after hematopoietic cell transplantation: is routine surveillance necessary?. Biol Blood Marrow Transplant. 2011 Oct. 17(10):1562-8. [View Abstract]
  33. Caserta MT, Hall CB, Schnabel K, Lofthus G, Marino A, Shelley L, et al. Diagnostic assays for active infection with human herpesvirus 6 (HHV-6). J Clin Virol. 2010 May. 48(1):55-7. [View Abstract]
  34. Engelmann I, Petzold DR, Kosinska A, Hepkema BG, Schulz TF, Heim A. Rapid quantitative PCR assays for the simultaneous detection of herpes simplex virus, varicella zoster virus, cytomegalovirus, Epstein-Barr virus, and human herpesvirus 6 DNA in blood and other clinical specimens. J Med Virol. 2008 Mar. 80(3):467-77. [View Abstract]
  35. Ihira M, Enomoto Y, Kawamura Y, Nakai H, Sugata K, Asano Y, et al. Development of quantitative RT-PCR assays for detection of three classes of HHV-6B gene transcripts. J Med Virol. 2012 Sep. 84(9):1388-95. [View Abstract]
  36. Merk J, Schmid FX, Fleck M, Schwarz S, Lehane C, Boehm S, et al. Fatal pulmonary failure attributable to viral pneumonia with human herpes virus 6 (HHV6) in a young immunocompetent woman. J Intensive Care Med. 2005 Sep-Oct. 20(5):302-6. [View Abstract]
  37. Harris RC. Long-term effects of human herpesvirus 6 infection. Pediatrics. 2008 Sep. 122(3):679. [View Abstract]
  38. Broccolo F, Drago F, Cassina G, Fava A, Fusetti L, Matteoli B, et al. Selective reactivation of human herpesvirus 6 in patients with autoimmune connective tissue diseases. J Med Virol. 2013 Nov. 85(11):1925-34. [View Abstract]
  39. Singh N. Infections with Human Herpesvirus 6, 7, and 8 after hematopoietic stem cell or solid organ transplantation. In: Bowden R, Ljungman P, Paya C. Transplant Infections. 2nd. Philadelphia: Lippincott Williams & Wilkins; 2004:365-374.
  40. Kumagai T, Yoshikawa T, Yoshida M, Okui T, Ihira M, Nagata N, et al. Time course characteristics of human herpesvirus 6 specific cellular immune response and natural killer cell activity in patients with exanthema subitum. J Med Virol. 2006 Jun. 78(6):792-9. [View Abstract]
  41. Tejada-Simon MV, Zang YC, Hong J, Rivera VM, Zhang JZ. Cross-reactivity with myelin basic protein and human herpesvirus-6 in multiple sclerosis. Ann Neurol. 2003 Feb. 53(2):189-97. [View Abstract]
  42. Rantala H, Mannonen L, Ahtiluoto S, Linnavuori K, Herva R, Vaheri A, et al. Human herpesvirus-6 associated encephalitis with subsequent infantile spasms and cerebellar astrocytoma. Dev Med Child Neurol. 2000 Jun. 42(6):418-21. [View Abstract]
  43. Epstein LG, Shinnar S, Hesdorffer DC, Nordli DR, Hamidullah A, et al. Human herpesvirus 6 and 7 in febrile status epilepticus: the FEBSTAT study. Epilepsia. 2012 Sep. 53(9):1481-8. [View Abstract]
  44. De Almeida Rodrigues G, Nagendra S, Lee CK, De Magalhães-Silverman M. Human herpes virus 6 fatal encephalitis in a bone marrow recipient. Scand J Infect Dis. 1999. 31(3):313-5. [View Abstract]
  45. Mendez JC, Dockrell DH, Espy MJ, Smith TF, Wilson JA, Harmsen WS, et al. Human beta-herpesvirus interactions in solid organ transplant recipients. J Infect Dis. 2001 Jan 15. 183(2):179-184. [View Abstract]
  46. Broccolo F, Drago F, Careddu AM, Foglieni C, Turbino L, Cocuzza CE, et al. Additional evidence that pityriasis rosea is associated with reactivation of human herpesvirus-6 and -7. J Invest Dermatol. 2005 Jun. 124(6):1234-40. [View Abstract]
  47. Peppercorn AF, Miller MB, Fitzgerald D, Weber DJ, Groben PA, Cairns BA. High-level human herpesvirus-6 viremia associated with onset of Stevens-Johnson syndrome: report of two cases. J Burn Care Res. 2010 Mar-Apr. 31(2):365-8. [View Abstract]
  48. Magalhães IM, Martins RV, Cossatis JJ, Cavaliere RM, Afonso LA, et al. Detection of human herpesvirus 6 and 7 DNA in saliva from healthy adults from Rio de Janeiro, Brazil. Mem Inst Oswaldo Cruz. 2010 Nov. 105(7):925-7. [View Abstract]
  49. Chang YL, Parker ME, Nuovo G, Miller JB. Human herpesvirus 6-related fulminant myocarditis and hepatitis in an immunocompetent adult with fatal outcome. Hum Pathol. 2009 May. 40(5):740-5. [View Abstract]
  50. Prezioso PJ, Cangiarella J, Lee M, Nuovo GJ, Borkowsky W, Orlow SJ, et al. Fatal disseminated infection with human herpesvirus-6. J Pediatr. 1992 Jun. 120(6):921-3. [View Abstract]
  51. Yoshida M, Nakamae H, Okamura H, Nishimoto M, Hayashi Y, Koh H, et al. Pericarditis Associated With Human Herpesvirus-6 Reactivation in a Patient After Unrelated Cord Blood Transplant. Exp Clin Transplant. 2015 Oct 14. [View Abstract]
  52. Lautenschlager I, Razonable RR. Human herpesvirus-6 infections in kidney, liver, lung, and heart transplantation: review. Transpl Int. 2012 May. 25(5):493-502. [View Abstract]
  53. Corti M, Villafañe MF, Trione N, Mamanna L, Bouzas B. Human herpesvirus 6: report of emerging pathogen in five patients with HIV/AIDS and review of the literature. Rev Soc Bras Med Trop. 2011 Jul-Aug. 44(4):522-5. [View Abstract]
  54. Eshki M, Allanore L, Musette P, Milpied B, Grange A, et al. Twelve-year analysis of severe cases of drug reaction with eosinophilia and systemic symptoms: a cause of unpredictable multiorgan failure. Arch Dermatol. 2009 Jan. 145(1):67-72. [View Abstract]
  55. Cacoub P, Musette P, Descamps V, Meyer O, Speirs C, Finzi L, et al. The DRESS syndrome: a literature review. Am J Med. 2011 Jul. 124(7):588-97. [View Abstract]
  56. Watanabe T, Nakashima H, Ohmatsu H, Sakurai N, Takekoshi T, Tamaki K. Detection of human herpesvirus-6 transcripts in carbamazepine-induced hypersensitivity syndrome by in situ hybridization. J Dermatol Sci. 2009 May. 54(2):134-6. [View Abstract]
  57. Sato T, Kuniba H, Matsuo M, Matsuzaka T, Moriuchi H. [Case of drug-induced hypersensitivity syndrome due to lamotrigine: demonstration of sequential reactivation of herpesviruses]. No To Hattatsu. 2012 Jan. 44(1):69-72. [View Abstract]
  58. Morimoto M, Watanabe Y, Arisaka T, Takada A, Tonogi M, Yamane GY, et al. A case of drug-induced hypersensitivity syndrome due to carbamazepine. Bull Tokyo Dent Coll. 2011. 52(3):135-42. [View Abstract]
  59. Watanabe H. Hypersensitivity syndrome due to trichloroethylene exposure: a severe generalized skin reaction resembling drug-induced hypersensitivity syndrome. J Dermatol. 2011 Mar. 38(3):229-35. [View Abstract]
  60. Fujiwara N, Namba H, Ohuchi R, Isomura H, Uno F, Yoshida M, et al. Monitoring of human herpesvirus-6 and -7 genomes in saliva samples of healthy adults by competitive quantitative PCR. J Med Virol. 2000 Jun. 61(2):208-13. [View Abstract]
  61. Norton RA, Caserta MT, Hall CB, Schnabel K, Hocknell P, Dewhurst S. Detection of human herpesvirus 6 by reverse transcription-PCR. J Clin Microbiol. 1999 Nov. 37(11):3672-5. [View Abstract]
  62. Sanders VJ, Felisan S, Waddell A, Tourtellotte WW. Detection of herpesviridae in postmortem multiple sclerosis brain tissue and controls by polymerase chain reaction. J Neurovirol. 1996 Aug. 2(4):249-58. [View Abstract]
  63. Härmä M, Höckerstedt K, Lyytikäinen O, Lautenschlager I. HHV-6 and HHV-7 antigenemia related to CMV infection after liver transplantation. J Med Virol. 2006 Jun. 78(6):800-5. [View Abstract]
  64. CARI. Donor sepsis. Nephrology. 2005;10(Suppl 4):S129-32.
  65. Ljungman P, Dahl H, Xu YH, Larsson K, Brytting M, Linde A. Effectiveness of ganciclovir against human herpesvirus-6 excreted in saliva in stem cell transplant recipients. Bone Marrow Transplant. 2007 Apr. 39(8):497-9. [View Abstract]
  66. Drago F, Vecchio F, Rebora A. Use of high-dose acyclovir in pityriasis rosea. J Am Acad Dermatol. 2006 Jan. 54(1):82-5. [View Abstract]
  67. Ohye T, Kawamura Y, Inagaki H, Yoshikawa A, Ihira M, Yoshikawa T, et al. A simple cytogenetic method to detect chromosomally integrated human herpesvirus-6. J Virol Methods. 2015 Nov 5. [View Abstract]
  68. Wipfler P, Dunn N, Beiki O, Trinka E, Fogdell-Hahn A. The Viral Hypothesis of Mesial Temporal Lobe Epilepsy - Is Human Herpes Virus-6 the Missing Link? A systematic review and meta-analysis. Seizure. 2018 Jan. 54:33-40. [View Abstract]
  69. Ljungman P, de la Camara R, Cordonnier C, Einsele H, Engelhard D, Reusser P, et al. Management of CMV, HHV-6, HHV-7 and Kaposi-sarcoma herpesvirus (HHV-8) infections in patients with hematological malignancies and after SCT. Bone Marrow Transplant. 2008 Aug. 42 (4):227-40. [View Abstract]
  70. Balsat M, Pillet S, Tavernier E, Cacheux V, Escuret V, Moluçon-Chabrot C, et al. Human herpesvirus 6 infection after autologous stem cell transplantation: A multicenter prospective study in adult patients. J Infect. 2019 Jul. 79 (1):36-42. [View Abstract]
  71. Razonable RR. Infections due to human herpesvirus 6 in solid organ transplant recipients. Curr Opin Organ Transplant. 2010 Dec. 15 (6):671-5. [View Abstract]
  72. Drago F, Broccolo F, Ciccarese G, Rebora A, Parodi A. Persistent pityriasis rosea: an unusual form of pityriasis rosea with persistent active HHV-6 and HHV-7 infection. Dermatology. 2015. 230 (1):23-6. [View Abstract]

Nine-month-old infant boy presented with one-day history of high-grade fever and irritability. In the emergency department, the patient underwent septic workup, including lumbar puncture, with normal cerebrospinal fluid analysis results. He was admitted to the hospital. High-grade fever abruptly resolved on day 3 of hospitalization. Within a few hours, erythematous, pink papular (roseola) nonpruritic rash appeared, mainly on trunk.

N-month-old infant boy presented with one-day history of high-grade fever and irritability. In the emergency department, the patient underwent septic workup, including lumbar puncture, with normal cerebrospinal fluid analysis results. He was admitted to the hospital. High-grade fever abruptly resolved on day 3 of hospitalization. Within a few hours, erythematous, pink papular (roseola) nonpruritic rash appeared, mainly on trunk. Patient was playful after supportive therapy. Antibiotics were discontinued after 2 days of negative cultures.

Nine-month-old infant boy presented with one-day history of high-grade fever and irritability. In the emergency department, the patient underwent septic workup, including lumbar puncture (adhesive bandage), with normal cerebrospinal fluid analysis results. He was admitted to the hospital.

Nine-month-old infant boy presented with one-day history of high-grade fever and irritability. In the emergency department, the patient underwent septic workup, including lumbar puncture, with normal cerebrospinal fluid analysis results. He was admitted to the hospital. High-grade fever abruptly resolved on day 3 of hospitalization. Within a few hours, erythematous, pink papular (roseola) nonpruritic rash appeared, mainly on trunk.

N-month-old infant boy presented with one-day history of high-grade fever and irritability. In the emergency department, the patient underwent septic workup, including lumbar puncture, with normal cerebrospinal fluid analysis results. He was admitted to the hospital. High-grade fever abruptly resolved on day 3 of hospitalization. Within a few hours, erythematous, pink papular (roseola) nonpruritic rash appeared, mainly on trunk. Patient was playful after supportive therapy. Antibiotics were discontinued after 2 days of negative cultures.