Human Herpesvirus 6 & 7

Human herpesvirus (HHV)-6 and HHV-7 are similar double-stranded DNA viruses belonging to the Herpesviridae family. Human herpesviruses are ubiquitous and infections are commonly contracted during childhood. Both HHV-6B and HHV-7 cause a common childhood illness known as roseola infantum (also known as roseola or 6th disease). Roseola is a self-limiting disease that presents with high fever, followed by a diffuse, rose-pink maculopapular rash. The diagnosis is clinical, and management is supportive.

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Classification

DNA virus classification flowchart

Identification of DNA viruses:
Viruses can be classified in many ways. Most viruses, however, will have a genome formed by either DNA or RNA. Viruses with a DNA genome can be further characterized as single or double stranded. “Enveloped” viruses are covered by a thin coat of cell membrane, which is usually taken from the host cell. If the coat is absent, however, the viruses are called “naked” viruses. Some enveloped viruses translate DNA into RNA before incorporating into the genome of the host cell.

Image by Lecturio. License: CC BY-NC-SA 4.0

General Characteristics and Epidemiology

Basic features of HHV-6 and HHV-7

  • Taxonomy:
    • Family: Herpesviridae
    • Subfamily: Betaherpesvirinae
    • Genus: Roseolovirus
    • Species:
      • Human betaherpesvirus 6A
      • Human betaherpesvirus 6B
      • Human betaherpesvirus 7
  • DNA viruses:
    • Linear
    • Double stranded
  • Structure:
    • DNA core
    • Icosahedral capsid
    • Tegument
    • Lipid envelope with glycoprotein spikes
Human herpesvirus 6

Electron micrograph of HHV-6 virions

Image: “Electron micrograph of one of the HHV6 species” by Bernard Kramarsky. License: Public Domain

Associated diseases

The clinical relevance of HHV-6A is not entirely known.

  • HHV-6B and HHV-7 are associated with:
    • Roseola infantum (also known as exanthem subitum, roseola, or 6th disease)
    • Acute febrile respiratory disease
    • Febrile seizures
    • Reactivation syndromes in transplant recipients:
      • Viremia
      • Encephalitis
      • Pneumonitis
      • Myocarditis
      • Hepatitis
    • Possible:
      • Pityriasis rosea
      • Lichen planus (HHV-7)

Epidemiology

  • HHV-6:
    • > 70% of adults are seropositive.
    • Infection generally occurs by the age of 2 years.
  • HHV-7: 
    • > 95% of adults are seropositive.
    • Infection often occurs in childhood.

Pathogenesis

Reservoir

Humans are the reservoir for HHV-6 and HHV-7.

Transmission

HHV-6 and HHV-7 are transmitted through contact with saliva.

Pathophysiology

  • Replication occurs in T lymphocytes.
  • Viral entry through:
    • HHV-6: CD46 receptor
    • HHV-7: CD4 receptor
  • Viral DNA is released into the nucleoplasm → production of viral proteins and replication
  • Lytic replication → cell death
  • Low-level persistent infection occurs in the salivary glands.
  • Latency:
    • HHV-6: occurs in monocytes
    • HHV-7: occurs in T lymphocytes

Clinical Presentation

Human herpesvirus-6 infections are usually mild and occur during childhood. Most HHV-7 infections are asymptomatic.

Roseola infantum

  • High fever:
    • Lasts approximately 3–5 days
    • Resolves abruptly
  • Rash:
    • Timing:
      • Follows resolution of fever
      • Lasts approximately 1–2 days
    • Appearance:
      • Maculopapular or macular
      • Rose-pink or red color
      • Blanching
    • Nonpruritic
    • Distribution:
      • Starts on neck and trunk
      • Spreads to face and extremities
  • Other manifestations:
    • Conjunctivitis
    • Edematous eyelids
    • Otitis media
    • Nagayama spots (erythematous uvulopalatoglossal papules)
    • Rhinorrhea
    • Cough
    • Diarrhea
    • Vomiting
    • Bulting fontanelle
    • Lymphadenopathy:
      • Cervical
      • Postauricular
      • Occipital

Diagnosis and Management

Diagnosis

The diagnosis is clinical, and testing is rarely indicated. An exception is made in the case of severe disease in immunocompromised individuals (e.g., encephalitis, myocarditis).

  • PCR to detect viral DNA
  • Serology
    • Indirect immunofluorescence
    • ELISA

Management

Treatment is generally not necessary, as symptoms are self-limiting. Patients with severe disease may be given:

  • Ganciclovir
  • Cidofovir
  • Foscarnet
  • Note: Data for these treatments are limited.

Comparison of Herpesviruses

The following table compares the 9 herpesviruses considered endemic in humans; there are 115 different total known species of herpesviruses, grouped into 3 families: 

  • Alpha (infect epithelial cells and produce latent infection in post-mitotic neurons)
  • Beta (infect and produce latent infection in a variety of cell types)
  • Gamma (produce latent infection, mainly in lymphoid cells)
Table: Comparison of the 9 herpesviruses considered endemic in humans
HHVCommon namePrimary target cellsLatency siteClinical presentation*
1
(alpha group)
HSV-1 Mucoepithelial cells Dorsal root ganglia
  • Gingivostomatitis
  • Keratitis
  • Herpetic whitlow
  • Encephalitis
  • Hepatitis
  • Esophagitis
  • Pneumonitis
2
(alpha group)
HSV-2
  • Genital herpes
  • Meningitis
  • Proctitis
3
(alpha group)
VZV
  • Chickenpox
  • Herpes zoster
4
(gamma group)
EBV
  • Epithelial cells
  • B cells
Memory B cells
  • Infectious mononucleosis
  • Hodgkin lymphoma
  • Burkitt lymphoma
  • Oral hairy leukoplakia
  • EBV-associated gastric cancer
5
(beta group)
CMV
  • Monocytes
  • Lymphocytes
  • Epithelial cells
Hematopoietic progenitor cells in bone marrow
  • CMV mononucleosis
  • CMV retinitis
  • CMV colitis
  • CMV encephalitis
6A, 6B
(beta group)
HHV-6 T cells Monocytes Roseola
7
(beta group)
HHV-7 T cells
8
(gamma group)
Kaposi sarcoma–associated herpesvirus
  • Lymphocytes
  • Epithelial cells
B cellsKaposi sarcoma
* Bold in “clinical presentation” column denotes an AIDS-defining illness.
CMV: cytomegalovirus
EBV: Epstein-Barr virus
HHV: Human herpesvirus
HSV: herpes simplex virus
KSHV: Kaposi sarcoma-associated herpesvirus
VZV: varicella-zoster virus

Comparison of Common Childhood Rashes

Table: Comparison of common childhood rashes
NumberOther names for the diseaseEtiologyDescription
1st disease
  • Measles
  • Rubeola
  • 14-day measles
  • Morbilli
Measles morbillivirus
  • Cough, coryza, conjunctivitis
  • Koplik’s spots (blue-white spots with a red halo) on the buccal membrane
  • Maculopapular rash begins on the face and behind the ears → spreads to trunk/extremities
2nd disease
  • Scarlet Fever
  • Scarlatina
Streptococcus pyogenes
  • Sandpaper-feeling maculopapular rash that begins on the neck and groin → spreads to trunk/extremities
  • Dark, hyperpigmented areas, especially in skin creases, called Pastia’s lines
  • Strawberry tongue: coated white membrane through which swollen, red papillae protrude
3rd disease
  • Rubella
  • German measles
  • 3-day measles
Rubella virus
  • Asymptomatic in 50% of cases
  • Fine macular rash on the face (behind the ears) → spreads to the neck, trunk, and extremities (spares palms/soles)
  • Forscheimer’s spots: Pinpoint red macules and petechiae can be seen over the soft palate/uvula.
  • Generalized tender lymphadenopathy
4th disease
  • Staphylococcal scalded skin syndrome
  • Filatow-Dukes’ disease
  • Ritter’s disease
Due to Staphylococcus aureus strains that make epidermolytic (exfoliative) toxin
  • Some believe that 4th disease is a misdiagnosis and, thus, nonexistent.
  • The term was dropped in the 1960s and is only used for medical trivia today.
  • Begins with a diffuse erythematous rash that usually starts around the mouth → fluid-filled bullae or cutaneous blisters → rupture and desquamate
  • Nikolsky’s sign: Applying pressure on the skin with a finger (stroking) results in sloughing off of upper layers.
5th diseaseErythema infectiosumErythrovirus or parvovirus B19 (Primate erythroparvovirus 1)
  • Facial erythema (“slapped-cheek” rash) that consist of red papules on the cheeks
  • Begins on the face → spreads to the extremities → extends to trunk/buttocks
  • Initially confluent, then becomes net-like or reticular as it clears
6th disease
  • Exanthem subitum
  • Roseola infantum
  • Rose rash of infants
  • 3-day fever
Human herpesvirus 6B or 7
  • Sudden onset of high fever
  • Nagayama spots: papular spots on the soft palate/uvula
  • Rash begins as fever resolves (the term “exanthem subitum” describes “surprise” of rash after the fever subsides).
  • Numerous rose-pink, almond-shaped macules on the trunk and neck → sometimes spreads to face/extremities

References

  1. Tremblay, C. (2020). Virology, pathogenesis, and epidemiology of human herpesvirus 6 infection. In Bond, S. (Ed.), UpToDate. Retrieved June 24, 2021, from https://www.uptodate.com/contents/virology-pathogenesis-and-epidemiology-of-human-herpesvirus-6-infection
  2. Tremblay, C., Brady, M.T. (2020). Human herpesvirus 6 infection in children: Clinical manifestations, diagnosis, and treatment. In Torchia, M.M. (Ed.), UpToDate. Retrieved June 24, 2021, from https://www.uptodate.com/contents/human-herpesvirus-6-infection-in-children-clinical-manifestations-diagnosis-and-treatment
  3. Tremblay, C. (2020). Clinical manifestations, diagnosis, and treatment of human herpesvirus 6 infection in adults. In Bond, S. (Ed.), UpToDate. Retrieved June 24, 2021, from https://www.uptodate.com/contents/clinical-manifestations-diagnosis-and-treatment-of-human-herpesvirus-6-infection-in-adults
  4. Tremblay, C. (2019). Human herpesvirus 7 infection. In Bond, S. (Ed.), UpToDate. Retrieved June 24, 2021, from https://www.uptodate.com/contents/human-herpesvirus-7-infection
  5. Tesini, B.L. (2019). Roseola infantum. [online] MSD Manual Professional Version. Retrieved June 24, 2021, from https://www.msdmanuals.com/professional/pediatrics/miscellaneous-viral-infections-in-infants-and-children/roseola-infantum
  6. King, O., Al Khalili, Y. (2020). Herpes virus type 6. [online] StatPearls. Retrieved June 24, 2021, from https://www.ncbi.nlm.nih.gov/books/NBK540998/
  7. Mullins, T.B., Krishnamurthy, K. (2020). Roseola infantum. [online] StatPearls. Retrieved June 24, 2021, from https://www.ncbi.nlm.nih.gov/books/NBK448190/
  8. Kiley, J.L., Blyth, D.M. (2019). Human herpesvirus 6 (HHV-6) infection. In Chandrasekar, P.H. (Ed.), Medscape. Retrieved June 24, 2021, from https://emedicine.medscape.com/article/219019-overview
  9. Wolz, M.M., Sciallis, G.F., Pittelkow, M.K. (2012). Human herpesviruses 6, 7, and 8 from a dermatologic perspective. In Mayo Clinical Proceedings. 87(10):1004-1014. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3538396/

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