Abstract
HHV-6 infection has been associated with neurological symptoms in children. Two variants
of human herpes virus 6, HHV-6A and HHV-6B, have been identified. Their role in neurological
infections is poorly understood. We studied 53 children with suspected encephalitis
for HHV-6A (strain GS) and HHV-6B (strain Z29) antibodies using an indirect immunofluorescence
test. Primary infection was separated from past infection by an IgG-avidity test.
The identified primary infections were studied for HHV-6 specific DNA by PCR. Forty-one
children of 53 had IgG antibodies to HHV-6. Six children had low avidity of HHV-6
IgG antibodies indicating acute primary infection; four to type A, one to B, and one
to both types. By serology, HHV-6 viral etiology was suggested in 6/53 (11.3%) of
cases. One of the six patients with primary infection had HHV-6 DNA in serum and two
in CSF. The children with primary HHV-6 infection were significantly younger than
the whole series, 2.3 years vs. 6.4 years. We conclude that primary HHV-6 infection
appears to be an important associated or causative agent in neurological infections
of young children, and it can be confirmed from a single serum specimen using the
IgG-avidity test.
Key words
encephalitis - serology - HHV-6A - HHV-6B - neurological - avidity
References
- 1
Ahlqvist J, Fotheringham J, Akhyani N, Yao K, Fogdell-Hahn A, Jacobson S.
Differential tropism of human herpesvirus 6 (HHV-6) variants and induction of latency
by HHV-6A in oligodendrocytes.
J Neurovirol.
2005;
11
384-394
- 2
Akhyani N, Berti R, Brennan MB, Soldan SS, Eaton JM, MacFarland HF. et al .
Tissue distribution and variant characterization of human herpesvirus (HHV)-6: increased
prevalence of HHV-6A in patients with multiple sclerosis.
J Infect Dis.
2000;
182
1321-1325
- 3
Asano Y, Yoshikawa T, Suga S, Kobayashi I, Nakashima T, Yazaki T. et al .
Clinical features of infants with primary human herpesvirus 6 infection (exanthem
subitum, roseola infantum).
Pediatrics.
1994;
93
104-108
- 4
Braun DK, Dominiguez G, Pellett PE.
Human herpesvirus 6.
Clin Microbiol Rev.
1997;
10
521-567
- 5
Byington CL, Zerr DM, Taggart EW, Nguy L, Hillyard DR, Carroll KC. et al .
Human herpesvirus 6 infection in febrile infants ninety days of age or younger.
Ped Infect Dis J.
2002;
21
996-999
- 6
Chan PK, Ng HK, Hui M, Cheng AF.
Prevalence and distribution of human herpesvirus 6 variants A and B in adult human
brain.
J Med Virol.
2001;
64
42-46
- 7
Clark DA, Nacheva EP, Leong HN, Brazma D, Li YT, Tsao EH. et al .
Transmission of integrated human herpesvirus 6 through stem cell transplantation:
implications for laboratory diagnosis.
J Infect Dis.
2006;
193
912-916
- 8
Cuomo L, Trivedi P, Cardillo MR, Gagliardi FM, Vecchione A, Caruso R. et al .
Human herpesvirus 6 in neoplastic and normal brain tissue.
J Med Virol.
2001;
63
45-51
- 9
Bolle L De, Naesens L, Clercq E De.
Update on human herpesvirus 6 biology, clinical features, and therapy.
Clin Microbiol Rev.
2005;
18
217-245
- 10
Dewhurst S, MacIntyre K, Schnabel K, Hall CB.
Human herpesvirus 6 (HHV-6) variant B accounts for the majority of symptomatic primary
HHV-6 infections in a population of U.S. infants.
J Clin Microbiol.
1993;
31
416-418
- 11
Fotheringham J, Akhyani N, Vortmeyer A, Donati D, Williams E, Oh U. et al .
Detection of active human herpesvirus 6 in the brain: correlation with polymerase
chain reaction detection of cerebrospinal fluid.
J Infect Dis.
2007;
195
450-454
- 12
Hall CB, Caserta MT, Schnabel K, Long C, Epstein LG, Insel RA. et al .
Persistence of human herpesvirus 6 according to site and variant: possible greater
neurotropism of variant A.
Clin Infect Dis.
1998;
26
132-137
- 13
Hall CB, Caserta MT, Schnabel KC, Boettrich C, MacDermott MP, Lofthus GK. et al .
Congenital infections with human herpesvirus 6 (HHV6) and human herpesvirus 7 (HHV7).
J Pediatr.
2004;
145
472-477
- 14
Hall CB, Long CE, Schnabel KC, Caserta MT, MacIntyre KM, Costanzo MA. et al .
Human herpesvirus-6 infection in children: A prospective study of complications and
reactivation.
N Engl J Med.
1994;
331
432-438
- 15
Hedman K, Lappalainen M, Söderlund M, Hedman L.
Avidity of IgG in serodiagnosis of infectious diseases.
Rev Med Microbiol.
1993;
4
123-129
- 16
Ishiguro N, Yamada S, Takahashi T, Takahashi Y, Togashi T, Okuno T. et al .
Meningo-encephalitis associated with HHV-6 related exanthema subitum.
Acta Paediatr Scand.
1990;
79
987-989
- 17
Jääskeläinen AJ, Piiparinen H, Lappalainen M, Koskiniemi M, Vaheri A.
Multiplex-PCR and oligonucleotide microarray for detection of eight different herpesviruses
from clinical specimens.
J Clin Virol.
2006;
37
83-90
- 18
Jones CM, Dunn HG, Thomas EE, Cone RW, Weber JM.
Acute encephalopathy and status epilepticus associated with human herpesvirus 6 infection.
Dev Med Child Neurol.
1994;
36
646-650
- 19
Koch WC.
Fifth (human parvovirus) and sixth (herpesvirus 6) diseases.
Curr Opin Infect Dis.
2001;
14
343-356
- 20 Koskiniemi M. CSF abnormalities in CNS viral infections. In: Handbook of Neurovirology
(Eds. McKendall RR, Stroop WG)
Neurologic Diseases and Therapy Series. Marcel Dekker Publishers, New York, Basel, Hong Kong 1994: 131-140
- 21
Koskiniemi M, Mannonen L, Kallio A, Vaheri A.
Luminometric microplate hybridization for detection of varicella-zoster virus PCR
product from cerebrospinal fluid.
J Virol Methods.
1997;
63
71-79
- 22
Koskiniemi M, Piiparinen H, Rantalaiho T, Eranko P, Färkkilä M, Raiha K. et al .
Acute central nervous system complications in varicella zoster virus infections.
J Clin Virol.
2002;
25
293-301
- 23
Koskiniemi M, Rantalaiho T, Piiparinen H, Bonsdorff CH von, Färkkilä M, Järvinen A.
et al .
Infections of the central nervous system of suspected viral origin: a collaborative
study from Finland.
J Neurovirol.
2001;
7
400-408
- 24
Koskiniemi M, Rautonen J, Lehtokoski-Lehtoniemi E, Vaheri A.
Epidemiology of encephalitis in children: a 20-year survey.
Ann Neurol.
1991;
29
492-497
- 25
Mannonen L, Herrgård E, Valmari P, Rautiainen P, Uotila K, Aine MR. et al .
Primary human herpesvirus 6 infection in the central nervous system can cause severe
disease.
Pediatr Neurol.
2007;
37
186-191
- 26
MacCullers JA, Lakeman FD, Whitley RJ.
Human herpesvirus 6 associated with focal encephalitis.
Clin Infect Dis.
1995;
21
571-576
- 27
Nitsche A, Muller CW, Radonic A, Landt O, Ellerbrok H, Pauli G. et al .
Human herpesvirus 6A DNA is detected frequently in plasma but rarely in peripheral
blood leukocytes of patients after bone marrow transplantation.
J Infect Dis.
2001;
183
130-133
- 28
Piiparinen H, Vaheri A.
Genotyping of herpes simplex viruses by polymerase chain reaction.
Arch Virol.
1991;
119
275-283
- 29
Portolani M, Pecorari M, Gennari W, Beretti F, Sabbatini AM, Casolari C. et al .
Case report: primary infection by human herpesvirus 6 variant A with the onset of
myelitis.
Herpes.
2006;
13
72-74
- 30
Portolani M, Pecorari M, Tamassia MG, Gennari W, Beretti F, Guaraldi G.
Case of fatal encephalitis by HHV-6 variant A.
J Med Virol.
2001;
65
133-137
- 31
Portolani M, Tamassia MG, Gennari W, Pecorari M, Beretti F, Alu M. et al .
Post-mortem diagnosis of encephalitis in a 75-year-old man associated with human herpesvirus-6
variant A.
J Med Virol.
2005;
77
244-248
- 32
Salahuddin SZ, Ablashi DV, Markham PD, Josephs SF, Sturzenegger S, Kaplan M. et al
.
Isolation of a new virus, HBLV, in patients with lymphoproliferative disorders.
Science.
1986;
234
596-601
- 33
Salonen MJH, Virtanen JO, Vaheri A, Koskiniemi M.
HHV-6 is emerging neuro- and lymphotropic virus with multiple disease associations.
J Pediatr Infect Dis.
2006;
1
137-142
- 34
Secchiero P, Zella D, Crowley RW, Gallo RC, Lusso P.
Quantitative PCR for human herpesviruses 6 and 7.
J Clin Microbiol.
1995;
33
2124-2130
- 35
Stoeckle MY.
The spectrum of human herpesvirus 6 infection: from roseola infantum to adult disease.
Ann Rev Med.
2000;
51
423-430
- 36
Tanaka-Taya K, Sashira J, Kurahashi H, Amo K, Miyagawa H, Kondo K. et al .
Human herpesvirus 6 (HHV-6) is transmitted from parent to child in an integrated form
and characterization of cases with chromosomally integrated HHV-6 DNA.
J Med Virol.
2004;
73
465-473
- 37
Ward KN, Andrews NJ, Verity CM, Miller E, Ross EM.
Human herpesviruses-6 and -7 each cause significant neurological morbidity in Britain
and Ireland.
Arch Dis Child.
2005;
90
619-623
- 38
Ward KN, Gray JJ, Fotheringham MW, Sheldon MJ.
IgG antibodies to human herpesvirus-6 in young children in avidity of antibody correlate
with time after infection.
J Med Virol.
1993;
39
131-138
- 39
Ward KN, Gray JJ, Joslin ME, Sheldon MJ.
Avidity of IgG antibodies to human herpesvirus-6 distinguishes primary from recurrent
infection in organ transplant recipients and excludes cross-reactivity with other
herpesviruses.
J Med Virol.
1993;
39
44-49
- 40
Ward KN, Thiruchelvam AD, Couto-Parada X.
Unexpected occasional persistence of high levels of HHV-6 DNA in sera: detection of
variants A and B.
J Med Virol.
2005;
76
563-570
- 41
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;
8594
1065-1067
- 42
Yamanishi K.
Human herpesvirus 6: an evolving story.
Herpes.
2000;
7
70-75
- 43
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;
352
768-776
- 44
Zerr DM.
Human herpesvirus 6: a clinical update.
Herpes.
2006;
13
20-24
Correspondence
J. O. Virtanen
Department of Virology
Haartman Institute
University of Helsinki
Haartmaninkatu 3
P.O.Box 21
00014 Helsinki
Finland
Phone: +358/9/1912 64 65
Fax: +358/9/1912 64 91
Email: oskari.virtanen@helsinki.fi