PEDIATRICS Vol. 99 No. 3 March 1997,
p. e4
Copyright ©1997 by the American Academy of Pediatrics
ELECTRONIC ARTICLE:
Clinical Features and Virological Findings in Children With
Primary Human Herpesvirus 7 Infection
, and
From the * Department of Pediatrics, Fujita Health University
School of Medicine, Toyoake, Aichi; and
the Nagai Pediatric Clinic,
Takamatsu, Kagawa, Japan.
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
ACKNOWLEDGMENTS
ABBREVIATIONS
REFERENCES
Objective. To elucidate clinical features of patients with primary human herpesvirus 7 (HHV-7) infection and serologic and virologic findings between HHV-7 and human herpesvirus 6 (HHV-6).
Materials and Methods. During a 19-month observation period, 71 infants and children (35 boys and 36 girls with a mean age of 14.5 months [range, 1 month to 48 months]) who had acute febrile respiratory illness with or without skin rash were examined clinically and virologically. Heparinized blood samples were used for isolation of HHV-6 and HHV-7 and detection of both virus DNA sequences by a nested polymerase chain reaction amplification. Both virus antibody activities were measured by an indirect immunofluorescent assay.
Results. HHV-7 infection was observed in 15 (6 boys and 9 girls with a mean age of 12.9 months [range, 7 months to 27 months]), 1 of 10 with upper respiratory infection and 14 (28%) of 50 with febrile exanthem, whereas HHV-6 infection was in 22 (44%) of the 50. Fever (37.5°C) was observed in all 15, with an average maximum body temperature of 38.7°C (range, 37.6°C to 39.8°C), which persisted for 2.9 days (range, 1 to 5 days). Papular, macular, or maculopapular rash was observed in 14 (93%) of the 15, which appeared on day 2.9 of fever (range, days 2 to 5) on the face, trunk, and extremities and persisted for 2.7 days (range, 1 to 5 days). A convulsive seizure that persisted for a few minutes developed in 1 patient on the first day of elevation of fever. HHV-6 antibody was demonstrated in 13 (87%), and a simultaneous significant increase to HHV-6 antibody titers was observed in 8 (53%) of the 15 during primary HHV-7 infection. HHV-7 and HHV-6 DNAs were almost always detected in mononuclear cells (MNCs) during acute and convalescent phases, whereas HHV-7 DNA was positive in some plasma samples obtained during the acute phase of the disease.
Conclusions. Primary HHV-7 infection occurred somewhat later than HHV-6, which was confirmed by the isolation of HHV-7 from blood and/or seroconversion to the virus. Clinical features of a virologically confirmed patient with primary HHV-7 infection were comparable with those of primary HHV-6 infection. Preexisting HHV-6 antibody increased significantly in the half of patients with primary HHV-7 infection. HHV-7 DNA was detected in peripheral blood MNCs and plasma in the acute phase and persisted in MNCs thereafter. human herpesvirus 7, human herpesvirus 6, exanthem subitum, roseola infantum, polymerase chain reaction.
Human herpesvirus 7 (HHV-7), isolated from purified and activated CD4+ T lymphocytes from the peripheral blood of a healthy individual in 1990 by Frenkel et al,1 has been recognized as a new lymphotropic herpesvirus.2 The virus was distinct from the six previously identified human herpesviruses and had limited homology to human cytomegalovirus and human herpesvirus 6 (HHV-6) by both molecular and immunological analyses.1,2 Healthy adults frequently shed the virus into saliva,3,4,6 and children are infected at a young age but somewhat later than when infected with HHV-6.5,7,8 Recent reports have suggested that primary infection with HHV-7 is linked to febrile illness with or without rash that resembles exanthem subitum or roseola infantum.9 However, thus far there is limited information about clinical manifestations of virologically confirmed cases. In the present study, we analyzed 15 patients with primary HHV-7 infection to clarify these points.
Patients
The study was conducted between September 1994 and March 1996 at Fujita Health University Hospital, Akita Hospital, and Nagai Pediatric Clinic. Seventy-one infants and children (35 boys and 36 girls with a mean age of 14.5 months [range, 1 month to 48 months]) who had acute febrile upper and lower respiratory illness with or without skin rash and whose parents agreed to blood sampling more than twice were enrolled in this study. Children with bacterial diseases were excluded from the subjects. Informed consent was obtained from parents of the subjects enrolled in this study after the project was thoroughly explained. A medical history and clinical signs and symptoms were recorded every day by parents for 10 to 14 days on a special form for this project, and we checked the record every 2 to 3 days. The first blood sample was collected within 7 days of the initial visit to our outpatient clinic, and we attempted to collect the convalescent sample 1 week to 2 months later. Children with a history of immune deficiency, those taking cytotoxic or immunosuppressive drugs, and those who had received immunoglobulin were not included in this study.Antibody Assays for HHV-7 and HHV-6
Antibody titers to HHV-7 and HHV-6 were measured by an indirect immunofluorescent assay, as described elsewhere.5,15Virus Isolation and Identification
Isolation of HHV-7 and HHV-6 was performed by cocultivating peripheral blood mononuclear cells (MNCs) from the patient with cord blood MNCs, as described elsewhere.5,6 Virus isolation was considered positive if the following findings were present: (1) round large cell formation of the cultured cells, and (2) specific immunofluorescence staining with the monoclonal antibody to HHV-710 or HHV-6.16Polymerase Chain Reaction (PCR) for HHV-7 and HHV-6
HHV-7 and HHV-6 DNAs were extracted from peripheral blood MNCs according to procedures reported elsewhere.12,17 The extracted HHV-6 DNA was amplified by the nested double PCR, as described previously.17 The outer and inner primers were made following the nucleotide sequences reported elsewhere.18,19 The primers amplify a DNA fragment of 751 base pairs (bp) of putative large tegument protein gene. The extracted HHV-7 DNA was amplified according to procedures reported elsewhere.2,12,17 The outer (HV7 and HV8) and inner (HV10 and HV11) primers were made following the nucleotide sequences reported by Berneman et al.2 These primers amplify a DNA fragment of 124 bp. The specific amplification was confirmed by using proven HHV-7 strains RK1 and JI2 and our own isolates.5 HHV-6 primers used did not amplify HHV-7 DNA, even at high copy number and vice versa. To avoid false-positive PCR results, disposable syringes and pipettes were used, and all reagents were assayed for the presence of HHV-7 and HHV-6 DNA sequences.Blood samples (145; 72 from acute phase and 73 from convalescent phase) were obtained from 71 subjects and used for virus isolation and antibody determination. HHV-7 was isolated from 10 peripheral blood MNCs of 9 patients. Seroconversion or fourfold increase in antibody titers to HHV-7 was observed in 15 of 71. On the other hand, HHV-6 was isolated from 12 of 71, and seroconversion or fourfold increase in antibody titers to HHV-6 was observed in 22 of 71. Thus, HHV-7 infection was confirmed in 15 (6 boys and 9 girls, with a mean age of 12.9 months [range, 7 months to 27 months]), 1 of 10 with upper respiratory infection and 14 (28%) of 50 with febrile exanthem, whereas HHV-6 infection was observed in 22 (44%) of the 50 (Table 1). The results of an isolation of HHV-7 and HHV-6 from peripheral blood MNCs and antibody responses to both viruses in the 15 patients are shown in Table 2. The infection was confirmed by virus isolation in the acute stage and seroconversion to the virus in 8 (cases 1 to 8) of the 15, virus isolation and a 16-fold increase in the antibody titers in 1 (case 9), seroconversion to the virus but no virus isolation from blood in 4 (cases 10 to 13), and a greater than fourfold increase in the antibody titers but no virus isolation in 2 (cases 14 and 15). Case 6 demonstrated seroconversion to both viruses, and case 12 showed seroconversion only to HHV-7.
|
Table 1. Clinical Diagnosis and Human Herpesviruses 7 and 6 Involvement in 71 Subjects With Acute Febrile Respiratory Illness* |
|
Table 2. Isolation of Human Herpesviruses 7 and 6 From Blood and Antibody Responses to the Viruses in Children With Primary Human Herpesvirus 7 Infection* |
Table 3.
Main Clinical Features and History of Exanthem Subitum in Children With
Primary Human Herpesvirus 7 Infection
Table 4.
Human Herpesviruses 6 and 7 DNAs in Blood of Children With Primary
Human Herpesvirus 7 Infection
In the present study, 15 patients were confirmed as having primary infection with HHV-7, and 14 of them had febrile exanthem. The frequency was 28% among 50 with febrile exanthem, comparable with the frequency reported recently by others, ie, 37%10 and 31%.13 A larger prospective cohort study will be required to know the precise frequency of primary HHV-7 infection in patients with febrile exanthem and that of febrile exanthem among primary HHV-7 infection in childhood. As suggested elsewhere,7,9,20 the present data also indicate that primary infection with HHV-7 occurs after development of ES, the primary infection with HHV-6, because 54% had a clinical history of ES and 87% had HHV-6 antibody at the acute stage of HHV-7 infection. This is supported further by the data that the mean age of the present 15 cases was 12.9 months, whereas that of 176 ES patients with primary HHV-6 infection was 7.3 months.21
Received for publication Jul 29, 1996; accepted Sep 26, 1996.
Reprint requests to (Y.A.) Department of Pediatrics, Fujita Health University School of Medicine, Toyoake, Aichi 470-11 Japan.
This work was supported in part by the grants from Fujita Health University and Grant-in-Aid for Scientific Research (C), The Ministry of Education, Science and Culture, Japan. Recombinant human interleukin-2 was kindly supplied by Takeda Chemical Industries, Ltd, Osaka, and monoclonal antibodies to HHV-7 and HHV-6 by Drs K. Yamanishi and T. Okuno, the Research Institute for Microbial Diseases, Osaka University, Osaka, Japan.
MNC, mononuclear cell. HHV-7, human herpesvirus 7. HHV-6, human herpesvirus 6. PCR, polymerase chain reaction. bp, base pair. ES, exanthem subitum.
-
Frenkel N,
Schirmer EC,
Wyatt LS,
Isolation of a new
herpesvirus from human CD4 + T cells.
Proc Natl Acad Sci
USA.
1990;
87:748-752 [Medline]
[Abstract/Free Full Text] -
Berneman ZN,
Ablashi DV,
Li G,
Human herpesvirus 7 is a
T-lymphotropic virus and is related to, but significantly different
from, human herpesvirus 6 and human cytomegalovirus.
Proc Natl
Acad Sci USA.
1992;
89:10552-10556 [Medline]
[Abstract/Free Full Text] - Black JB, Inoue N, Kite-Powell K, Zaki S, Pellett PE Frequent isolation of human herpesvirus 7 from saliva. Virus Res. 1993; 29:91-98 [Medline][CrossRef][Medline]
- Hidaka Y, Liu Y, Yamamoto M, Frequent isolation of human herpesvirus 7 from saliva samples. J Med Virol. 1993; 40:343-346 [Medline][Medline]
- Yoshikawa T, Asano Y, Kobayashi I, Seroepidemiology of human herpesvirus 7 in healthy children and adults in Japan. J Med Virol. 1993; 41:319-323 [Medline][Medline]
-
Wyatt LS,
Frenkel N
Human herpesvirus 7 is a constitutive inhabitant
of adult human saliva.
J Virol.
1992;
66:3206-3209 [Medline]
[Abstract/Free Full Text] -
Wyatt LS,
Rodriguez WJ,
Balachandran N,
Frenkel N
Human herpesvirus 7:
antigenic properties and prevalence in children and adults.
J Virol.
1991;
65:6260-6265 [Medline]
[Abstract/Free Full Text] - Clark DA, Freeland JML, Makie PLK, Jarrett RF, Onions DE Prevalence of antibody to human herpesvirus 7 by age. J Infect Dis. 1993; 168:251-252 [Medline][Medline]
- Ueda K, Kusuhara K, Okada K, Primary human herpesvirus 7 infection and exanthem subitum. Pediatr Infect Dis J. 1994; 13:167-168 [Medline][Medline]
- Tanaka K, Kondo T, Torigoe S, Okada S, Mukai T, Yamanishi K Human herpesvirus 7: another causal agent for roseola (exanthem subitum). J Pediatr. 1994; 125:1-5 [Medline][CrossRef][Medline]
- Hidaka Y, Okada K, Kusuhara K, Miyazaki C, Tokunaga K, Ueda K Exanthem subitum and human herpesvirus 7 infection. Pediatr Infect Dis J. 1994; 11:1010-1011
-
Asano Y,
Suga S,
Yoshikawa T,
Yazaki T,
Uchikawa T
Clinical features
and viral excretion in an infant with primary human herpesvirus 7 infection.
Pediatrics.
1995;
95:187-190 [Medline]
[Abstract/Free Full Text] -
Torigoe S,
Kumamoto T,
Koide W,
Taya K,
Yamanishi K
Clinical
manifestations associated with human herpesvirus 7 infection.
Arch Dis Child.
1995;
72:518-519 [Medline]
[Abstract/Free Full Text] - Portolani M, Cermelli C, Mirandola P, Di Luca D Isolation of human herpesvirus 7 from an infant with febrile syndrome. J Med Virol. 1995; 45:282-283 [Medline][Medline]
- Suga S, Yoshikawa T, Asano Y, Yazaki T, Ozaki T Neutralizing antibody assay for human herpesvirus-6. J Med Virol. 1990; 30:14-19 [Medline][Medline]
- Okuno T, Asada H, Shiraki K, Takahashi M, Yamanishi K Analysis of a glycoprotein of human herpesvirus 6 (HHV-6) using monoclonal antibodies. Virology. 1990; 176:625-628 [Medline][CrossRef][Medline]
- Suga S, Yoshikawa T, Asano Y, Clinical and virological analyses of 21 infants with exanthem subitum (roseola infantum) and central nervous system complications. Ann Neurol. 1993; 33:597-603 [Medline][CrossRef][Medline]
-
Aubin JT,
Collandre H,
Candotti D,
Several groups among human
herpesvirus 6 strains can be distinguished by Southern blotting and
polymerase chain reaction.
J Clin Microbiol.
1991;
29:367-372 [Medline]
[Abstract/Free Full Text] -
Dewhurst S,
McIntyre 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 [Medline]
[Abstract/Free Full Text] - Cermelli C, Fabio G, Montorsi M, Sabbatini AM, Portolani M Prevalence of antibodies to human herpesviruses 6 and 7 in early infancy and age at primary infection. Microbiologica. 1996; 19:1-8[Medline]
-
Asano Y,
Yoshikawa T,
Suga S,
Clinical features of infants with
primary human herpesvirus 6 infection (exanthem subitum, roseola
infantum).
Pediatrics.
1994;
93:104-108 [Medline]
[Abstract/Free Full Text] -
Foa-Tomasi L,
Avitabile E,
Ke K,
Campadelli-Fiume
Polyvalent and
monoclonal antibodies identify major immunogenic proteins specific for
human herpesvirus 7-infected cells and have weak cross-reactivity with
human herpesvirus 6.
J Gen Virol.
1994;
75:2719-2727 [Medline]
[Abstract/Free Full Text] -
Yasukawa M,
Yakushijin Y,
Furukawa M,
Fujita S
Specificity analysis of
human CD4+ T-cell clones directed against human herpesvirus 6 (HHV-6),
HHV-7, and human cytomegalovirus.
J Virol.
1993;
67:6259-6264 [Medline]
[Abstract/Free Full Text] - Suga S, Yoshikawa T, Asano Y, Yazaki T, Yoshida S Simultaneous infection of human herpesvirus 6 and measles virus in infants. J Med Virol. 1990; 31:306-311 [Medline][Medline]
-
Hashida T,
Komura E,
Yoshida M,
Hepatitis in association with
human herpesvirus 7 infection.
Pediatrics.
1995;
96:783-785 [Medline]
[Abstract/Free Full Text] - Frenkel N, Wyatt LS HHV-6 and HHV-7 as exogenous agents in human lymphocytes. Dev Biol Stand. 1992; 76:259-265 [Medline][Medline]
- Frenkel N, Roffman E. Human herpesvirus 7. In: Fields BN, Knipe DM, Howley PM, et al, eds. Fields Virology, 3rd ed. Philadelphia: Lippincott-Raven Publishers; 1996:2609-2622
- Gopal MR, Thomson BJ, Fox J, Tedder RS, Honess RW Detection by PCR of HHV-6 and EBV DNA in blood and oropharynx of healthy adults and HIV-seropositives. Lancet. 1990; 336:1598-1599
-
Kondo K,
Kondo T,
Okuno T,
Takahashi M,
Yamanishi K
Latent human
herpesvirus 6 infection of human monocytes/macrophages.
J
Gen Virol.
1991;
72:1401-1408 [Medline]
[Abstract/Free Full Text] -
Cone RW,
Huang MW,
Ashley R,
Corey L
Human herpesvirus 6 DNA in
peripheral blood cells and saliva from immunocompetent individuals.
J Clin Microbiol.
1993;
31:1262-1267 [Medline]
[Abstract/Free Full Text] - Luca DD, Zorzenon M, Mirandora P, Colle B, Botta GA, Cassai E Human herpesvirus 6 and human herpesvirus 7 in chronic fatigue syndrome. J Clin Microbiol. 1995; 33:1660-1661[Abstract]
- Wilborn W, Schmidt CA, Lorenz F, Human herpesvirus 7 in blood donors: detection by the polymerase chain reaction. J Med Virol. 1995; 47:65-69[Medline]
- Kidd IM, Clark DA, Ait-Khaled M, Griffiths PD, Emery VC Measurement of human herpesvirus 7 load in peripheral blood and saliva of healthy subjects by quantitative polymerase chain reaction. J Infect Dis. 1996; 174:396-401 [Medline][Medline]
- Suga S, Yazaki T, Kajita Y, Ozaki T, Asano Y Detection of human herpesvirus 6 DNAs in samples from several body sites of patients with exanthem subitum and their mothers by polymerase chain reaction assay. J Med Virol. 1995; 46:52-55 [Medline] [Medline]
Pediatrics (ISSN 0031 4005). Copyright ©1997 by the American Academy of Pediatrics
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||




