HUMAN HERPESVIRUS-& AND 7 DISEASE

Primary HHV-6 and HHV-7 infections cause exanthema subitum or roseola infantum,
characterized by high fever in a healthy infant (9 to 12 months old), defervescence in
3 days followed by sudden appearance of exanthem.

Etiology. HHV-6 (variants 6A and 6B) and HHV-7 share genetic, biologic, and
immunologic features and are T cell tropic. At birth, most children have passively
transferred anti-HHV-6 and anti-7 lgG.Primary infection is acquired via ropharyngeal
secretions. HHV-6 antibodies reach a nadir at 4 to 7 months and increase throughout
infancy. By 12 months, two-thirds of children become infected,with peak antibody
levels reached at 2 to 3 years of age. Similarly, HHV-7 antibodies reach nadir at
6 months, with level peaking at 3 to 4years of age. Latent infection may persist for
the lifetime of the individual.

Pathogenesis. HHV-68 causes exanthema subitum; pathogenesis of the exanthema

is most likely immune response to viral antigens. HHV-68 reactivation occurs in
transplant recipients and can cause encephalitis, bone marrow suppression, and
pneumonitis.

Pathogenesis (medscape)

In the primary infection, replication of the virus occurs in the leukocytes and the salivary
glands. HHV-6 is present in saliva. A study monitoring HHV-6 and HHV-7 DNA in saliva
samples during the acute and convalescent phases demonstrated a significantly higher rate of
detection in children aged 3-9 years versus adults, suggesting that children in the
convalescent phase of roseola infantum are the more probable source of infection. [3] Early
invasion of the CNS is believed to occur, thus accounting for seizures and other CNS
complications. Evidence suggests that high serum levels of matrix metalloproteinase 9 and
tissue inhibitor of metalloproteinases 1 in infants infected with HHV-6 may lead to blood-
brain barrier dysfunction, which may result in febrile seizures. [4] Study of cerebrospinal fluid
levels of interleukin 1 and basic fibroblast growth factor may indicate a role in contributing
to HHV-6B growth and the onset of encephalitis. [5] Although rare in the primary disease of
infancy, generalized organ involvement has been reported with gastrointestinal, hematopathic
syndromes; hepatitis; and hepatosplenomegaly.

Following the acute primary infection, HHV-6 remains latent in lymphocytes and monocytes
and has been found in low levels in many tissues. Peripheral blood mononuclear cell cultures
develop enlarged balloonlike cells. Cells supporting virus growth are CD4+ T lymphocytes.
HHV-6 down-regulates the host immune response through several mechanisms, including
molecular mimicry by production of functional chemokine and chemokine receptors.

The two variants of HHV-6 are A and B. The genomes of HHV-6A/B have been sequenced.
HHV-6B, the main cause of roseola, consists of 97 unique genes. CD46 is the cell receptor
for HHV-6, which imparts the virus' broad tissue tropism.

A possible association of HHV-6 and multiple sclerosis has been suggested but is still
inconclusive. HHV-6 has been isolated in Kaposi sarcoma (caused by human herpesvirus 8),
in which it may contribute to tumor progression. HHV-6 may facilitate oncogenic potential in
lymphoma and has been associated with chronic fatigue syndrome.
Christopher R Gorman, MD Avenues Dermatology, Private Practice. Roseola infantum.

CLINICAL MANIFESTATION

INCUBATION PERIOD. The incubation period of roseola infantum ( Figure 14-19 ) is 12

days, with a range of 5 to 15 days.

PRODROMAL SYMPTOMS. There is a sudden onset of high fever of 103 to 106 F, with
few or minor symptoms. Most children appear inappropriately well for the degree of
temperature elevation, but they may experience slight anorexia or one or two episodes of
vomiting, running nose, cough, and hepatomegaly. Seizures (but more frequently general
cerebral irritability) may occur before the eruptive phase. Most recover without sequelae.
Cases of encephalitis/ encephalopathy with abnormal electroencephalograms and cerebral
computed tomograms have been reported; epilepsy developed in one case and in another case
the patient died. HHV-6 DNA has been detected in the cerebrospinal fl uid (CSF); this
suggests that HHV-6 may invade the brain during the acute phase. HHV-6 infection should
be suspected in infants with febrile convulsions, even those without the exanthem. Mild-to-
moderate lymphadenopathy, usually in the occipital regions, begins at the onset of the febrile
period and persists until after the eruption has subsided.

ERUPTIVE PHASE. The rash begins as the fever subsides. The term exanthem subitum
indicates the sudden surprise of the blossoming rash after the fall of the fever. Numerous
pale pink, almond-shaped macules appear on the trunk and neck, become confl uent, and then
fade in a few hours to 2 days without scaling or pigmentation ( Figures 14-20 and 14-21 ).
The exanthem may resemble rubella or measles, but the pattern of development, distribution,
and associated symptoms of these other exanthematous diseases are different.

PRODROME High fever ranging from 38.9" to40.6"C. Remains consistently high, with
morning remission, until the fourth day, when it falls precipitously to normal, coincident with
the appearance of rash. Infant remarkably well despite high fever. Asymptomatic primary
HHV-6 and HHV-7 infection is common.

EXANTHEM SUBITUM OR ROSEOLA INFANTUM

Small blanchable pink macules and papules, 1 to 5 mm in diameter (Fig. 27-59). Lesions
may remain discrete or become confluent. Distribution: Trunk and neck.

Exanthema subltum Multiple, blanch able macules and papules

on the back of a febrile child, which appeared as the temperature fell.

GENERAL FINDINGS Absent in presence of high fever. Febrile seizures are common.

DIFFERENTIAL DIAGNOSIS
Other viral exanthems, ACDE, scarlet fever. SEROLOGY Demonstration oflgM anti-HHV-
6 or anti-HHV-7 antibodies or IgGseroconversion.
DIAGNOSIS
Usually made on clinical findings.

COURSE
Exanthem subitum is self-limited with rare sequelae. In some cases, high fever may be
associated with seizures. Intussusception associated with hyperplasia of intestinal
lymphoid tissue and hepatitis reported. As with other HHV infections, HHV-6 and
HHV-7 persist throughout the life of the patient. The role ofHHV-6 and HHV-7 in
the pathogenesis of pityriasis rosea is being investigated.
Therapeutic implications and future research directions
The HHV6 disease associations with roseola in children and widespread
organ involvement in immunosuppressed individuals are well established.
Unfortunately, acyclovir and its derivatives have little antiherpesviral activity against
HHV-6 and HHV-7 (Takahashi et al, 1997). Foscarnet, ganciclovir, and cidofovir
have some activity at high concentrations, but all of these medications are of limited
practical use because of the need to administer them intravenously or the potentially
worrisome sideeffects.
Thus, patients with active HHV-6 replication and roseola should not be treated
with antiherpesviral therapy. These drugs, however, should be considered in patients
with end organ dysfunction or widespread systemic disease. At this time, patients
with PR, whether the association with HHV-7 is conrmed or refuted, should also not
be treated with antiherpesviral therapy. Further study is needed to determine the
roles of herpesviruses in the etiologies of both PR and severe drug-induced
hypersensitivity reactions.

TREATMENT. Control temperature with aspirin and provide reassurance. HHV-6 is inhibited by several antiviral
drugs in the laboratory, including ganciclovir and foscarnet. Treatment may be considered for patients with serious
HHV-6-associated disease confi rmed with virologic tests.

Complications
In roseola infantum, complications are rare. Given that seroconversion is practically
universal, finding any of the complications that have been reported in the gastrointestinal,
central nervous, pulmonary, and hematopoietic systems is rare.

Children who have seizures with roseola are not expected to have further febrile or nonfebrile
seizures.

Thomas p habis. Clinical dermatology fifth edition. Elsevier. 2010 Page 566