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Preliminary Communication |

Primary Human Herpesvirus 8 Infection in Immunocompetent Children FREE

Massimo Andreoni, MD; Loredana Sarmati, MD; Emanuele Nicastri, MD; Gamal El Sawaf, MD; Mahmoud El Zalabani, MD; Ilaria Uccella, MD; Roberto Bugarini, DStat; Saverio G. Parisi, MD; Giovanni Rezza, MD
[+] Author Affiliations

Author Affiliations: Department of Public Health, University of Tor Vergata (Drs Andreoni, Sarmati, Uccella, and Parisi), Istituto Nazionale per le Malattie Infettive, IRCCS Lazzaro Spallanzani (Dr Nicastri), AIDS and STD Unit, Laboratory of Epidemiology and Biostatistics, Istituto Superiore di Sanità (Drs Bugarini and Rezza), Rome, Italy; and Medical Research Institute, Alexandria University, Alexandria, Egypt (Drs El Sawaf and El Zalabani).


JAMA. 2002;287(10):1295-1300. doi:10.1001/jama.287.10.1295.
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Published online

Context Human herpesvirus 8 (HHV-8) infection causes Kaposi sarcoma and lymphoproliferative disorders in immunosuppressed adults. Its manifestations in immunocompetent hosts are unknown.

Objectives To determine whether HHV-8 primary infection is symptomatic in immunocompetent children and to identify the epidemiological and virological correlates of HHV-8 infection.

Design and Setting Prospective cohort study conducted in the pediatric emergency department of a hospital in Alexandria, Egypt, between December 1, 1999, and April 30, 2000.

Patients Eighty-six children aged 1 to 4 years who were evaluated for a febrile syndrome of undetermined origin.

Main Outcome Measures Serological assay and polymerase chain reaction of blood and saliva samples for HHV-8. Information on potential risk factors for HHV-8 infection was also collected.

Results Thirty-six children (41.9%) were seropositive; HHV-8 DNA sequences were detected in 14 (38.9%) of these 36 children (detected in saliva in 11 of 14). Significant associations were found between HHV-8 infection and close contact with at least 2 other children in the community (36 of 63 vs 6 of 23 for <2 children; adjusted odds ratio [OR], 3.50; 95% confidence interval [CI], 1.11-12.22) and admission to the emergency department in December or January (28 of 47 vs 14 of 39 for February-April; adjusted OR, 3.15; 95% CI, 1.23-8.58). Six children had suspected primary HHV-8 infection; all but 1 had a febrile cutaneous craniocaudal maculopapular rash, which was more common among these children (5 of 6 vs 10 of 75; P<.001). For 3 of these 6 children, a second blood sample was obtained after the convalescence phase, and all 3 seroconverted for HHV-8.

Conclusions Primary infection with HHV-8 may be associated with a febrile maculopapular skin rash among immunocompetent children. The finding of HHV-8 DNA sequences in saliva supports the hypothesis that transmission through saliva is the main mode of transmission in the pediatric age group.

Human herpesvirus 8 (HHV-8) has recently been implicated in the development of Kaposi sarcoma, primary effusion B-cell lymphoma, and multicentric Castleman disease of the plasma-cell type.13 Its consistent detection in tissue lesions of Kaposi sarcoma and the results of epidemiological studies47 confirm that HHV-8 is the cause of this neoplasm.

In countries with a low prevalence of HHV-8 infection, such as the United States, the infection appears to be restricted to sexually active homosexual men, and its prevalence appears to be low among children.8 In high-prevalence areas, such as many African countries, the infection is also widespread among children.5,9 However, the risk factors for acquiring HHV-8 infection are still uncertain, although saliva exchange is likely to play a major role.10

It is unknown whether primary HHV-8 infection causes specific clinical manifestations in immunocompetent hosts, partly because HHV-8 seroconversion has usually been documented retrospectively5,11 and among immunosuppressed adults. Although the development of Kaposi sarcoma and lymphoproliferative disorders is a late event strictly corresponding to immunosuppression related to HIV (human immunodeficiency virus) infection, the use of immunosuppressive drugs for organ transplantation, and aging, to the best of our knowledge, only 3 cases of symptomatic primary disease have been reported. The first was an HIV-infected patient who had developed transient angiolymphoid hyperplasia characterized by transient fever, arthralgia, cervical adenopathy, and splenomegaly during primary HHV-8 infection.12 The other 2 cases were patients who had each received a kidney from the same HHV-8–seropositive cadaveric donor: HHV-8 seroconversion and viremia occurred with disseminated Kaposi sarcoma in one patient and with bone marrow failure with plasmocytosis in the other.13

The objectives of this study were to determine whether primary HHV-8 infection can cause specific clinical manifestations in immunocompetent children and to identify the epidemiological and virological correlates of HHV-8 infection.

Chang Y, Cesarman E, Pessin MS.  et al.  Identification of herpesvirus-like DNA sequences in AIDS-associated Kaposi's sarcoma.  Science.1994;266:1865-1869.
Cesarman E, Chang Y, Moore PS, Said JW, Knowles DM. Kaposi's sarcoma-associated herpesvirus-like DNA sequences in AIDS-related body-cavity-based lymphomas.  N Engl J Med.1995;332:1186-1191.
Soulier J, Grollet L, Oksenhendler E.  et al.  Kaposi's sarcoma-associated herpesvirus-like DNA sequences in multicentric Castleman's disease.  Blood.1995;86:1276-1280.
Kedes DH, Operskalski E, Busch M, Kohn R, Flood J, Ganem D. The seroepidemiology of human herpesvirus 8 (Kaposi's sarcoma associated herpesvirus): distribution of infection in KS risk groups and evidence for sexual transmission.  Nat Med.1996;2:918-924.
Gao SJ, Kingsley L, Li M.  et al.  KSHV antibodies among Americans, Italians, and Ugandans with and without Kaposi's sarcoma.  Nat Med.1996;2:925-928.
Martin JN, Osmond DH. Invited commentary: determining specific sexual practices associated with human herpesvirus 8 transmission.  Am J Epidemiol.2000;151:225-229.
Rezza G, Andreoni M, Dorrucci M.  et al.  Human herpesvirus 8 seropositivity and risk of Kaposi's sarcoma and other acquired immunodeficiency syndrome-related diseases.  J Natl Cancer Inst.1999;91:1468-1474.
Blauvelt A, Sei S, Cook PM, Schultz TF, Jeang KT. Human herpesvirus 8 infection occurs following adolescence in United States.  J Infect Dis.1997;176:771-774.
Andreoni M, El-Sawaf G, Rezza G.  et al.  High seroprevalence of antibodies to human herpesvirus-8 in Egyptian children: evidence of nonsexual transmission.  J Natl Cancer Inst.1999;91:465-469.
Pauk J, Huang ML, Brodie SJ.  et al.  Mucosal shedding of human herpesvirus 8 in men.  N Engl J Med.2000;343:1369-1377.
Regamey N, Tamm M, Wernli M.  et al.  Transmission of human herpesvirus 8 infection from renal-transplant donors to recipients.  N Engl J Med.1998;339:1358-1363.
Oksenhendler E, Cazals-Hatem D, Schulz TF.  et al.  Transient angiolymphoid hyperplasia and Kaposi's sarcoma after primary infection with human herpesvirus 8 in a patient with human immunodeficiency virus infection.  N Engl J Med.1998;338:1585-1590.
Luppi M, Barozzi P, Schultz TF.  et al.  Bone marrow failure associated with human herpesvirus 8 infection after transplantation.  N Engl J Med.2000;343:1378-1385.
World Medical Association.  Declaration of Helsinki: ethical principles for medical research involving human subjects.  JAMA.2000;284:3043-3046.
Lock MJ, Griffiths PD, Emery VC. Development of a quantitative competitive polymerase chain reaction for human herpesvirus 8.  J Virol Methods.1997;64:19-26.
Schatz O, Monini P, Bugarini R.  et al.  Kaposi's sarcoma-associated herpesvirus serology in Europe and Uganda: multicenter study with multiple and novel assays.  J Med Virol.2001;65:123-132.
Luppi M, Barozzi P, Schultz TF.  et al.  Nonmalignant diseases associated with human herpevirus 8 reactivation in patients who have undergone autologous peripheral blood stem cells transplantation.  Blood.2000;96:2355-2357.
Goudsmit J, Renwick N, Dukers NH.  et al.  Human herpesvirus 8 infections in the Amsterdam Cohort Studies (1984-1997): analysis of seroconversions to ORF65 and ORF73.  Proc Natl Acad Sci U S A.2000;97:4838-4843.
Pruksananonda P, Hall CB, Insel RA.  et al.  Primary human herpesvirus 6 infection in young children.  N Engl J Med.1992;326:1445-1450.
Asano Y, Yoshikawa T, Suga S.  et al.  Viremia and neutralizing antibody response in infants with exanthem subitum.  J Pediatr.1989;114:535-539.
Mayama S, Cuevas LE, Sheldon J.  et al.  Prevalence and transmission of Kaposi's sarcoma-associated herpesvirus (human herpesvirus 8) in Ugandan children and adolescents.  Int J Cancer.1998;77:817-820.
Calabro ML, Gasperini P, Fiore JR, Barberiato M, Angarano G, Chieco-Bianchi L. Intrafamilial transmission of human herpesvirus 8.  J Natl Cancer Inst.2001;93:154-156.

Figures

Tables

References

Chang Y, Cesarman E, Pessin MS.  et al.  Identification of herpesvirus-like DNA sequences in AIDS-associated Kaposi's sarcoma.  Science.1994;266:1865-1869.
Cesarman E, Chang Y, Moore PS, Said JW, Knowles DM. Kaposi's sarcoma-associated herpesvirus-like DNA sequences in AIDS-related body-cavity-based lymphomas.  N Engl J Med.1995;332:1186-1191.
Soulier J, Grollet L, Oksenhendler E.  et al.  Kaposi's sarcoma-associated herpesvirus-like DNA sequences in multicentric Castleman's disease.  Blood.1995;86:1276-1280.
Kedes DH, Operskalski E, Busch M, Kohn R, Flood J, Ganem D. The seroepidemiology of human herpesvirus 8 (Kaposi's sarcoma associated herpesvirus): distribution of infection in KS risk groups and evidence for sexual transmission.  Nat Med.1996;2:918-924.
Gao SJ, Kingsley L, Li M.  et al.  KSHV antibodies among Americans, Italians, and Ugandans with and without Kaposi's sarcoma.  Nat Med.1996;2:925-928.
Martin JN, Osmond DH. Invited commentary: determining specific sexual practices associated with human herpesvirus 8 transmission.  Am J Epidemiol.2000;151:225-229.
Rezza G, Andreoni M, Dorrucci M.  et al.  Human herpesvirus 8 seropositivity and risk of Kaposi's sarcoma and other acquired immunodeficiency syndrome-related diseases.  J Natl Cancer Inst.1999;91:1468-1474.
Blauvelt A, Sei S, Cook PM, Schultz TF, Jeang KT. Human herpesvirus 8 infection occurs following adolescence in United States.  J Infect Dis.1997;176:771-774.
Andreoni M, El-Sawaf G, Rezza G.  et al.  High seroprevalence of antibodies to human herpesvirus-8 in Egyptian children: evidence of nonsexual transmission.  J Natl Cancer Inst.1999;91:465-469.
Pauk J, Huang ML, Brodie SJ.  et al.  Mucosal shedding of human herpesvirus 8 in men.  N Engl J Med.2000;343:1369-1377.
Regamey N, Tamm M, Wernli M.  et al.  Transmission of human herpesvirus 8 infection from renal-transplant donors to recipients.  N Engl J Med.1998;339:1358-1363.
Oksenhendler E, Cazals-Hatem D, Schulz TF.  et al.  Transient angiolymphoid hyperplasia and Kaposi's sarcoma after primary infection with human herpesvirus 8 in a patient with human immunodeficiency virus infection.  N Engl J Med.1998;338:1585-1590.
Luppi M, Barozzi P, Schultz TF.  et al.  Bone marrow failure associated with human herpesvirus 8 infection after transplantation.  N Engl J Med.2000;343:1378-1385.
World Medical Association.  Declaration of Helsinki: ethical principles for medical research involving human subjects.  JAMA.2000;284:3043-3046.
Lock MJ, Griffiths PD, Emery VC. Development of a quantitative competitive polymerase chain reaction for human herpesvirus 8.  J Virol Methods.1997;64:19-26.
Schatz O, Monini P, Bugarini R.  et al.  Kaposi's sarcoma-associated herpesvirus serology in Europe and Uganda: multicenter study with multiple and novel assays.  J Med Virol.2001;65:123-132.
Luppi M, Barozzi P, Schultz TF.  et al.  Nonmalignant diseases associated with human herpevirus 8 reactivation in patients who have undergone autologous peripheral blood stem cells transplantation.  Blood.2000;96:2355-2357.
Goudsmit J, Renwick N, Dukers NH.  et al.  Human herpesvirus 8 infections in the Amsterdam Cohort Studies (1984-1997): analysis of seroconversions to ORF65 and ORF73.  Proc Natl Acad Sci U S A.2000;97:4838-4843.
Pruksananonda P, Hall CB, Insel RA.  et al.  Primary human herpesvirus 6 infection in young children.  N Engl J Med.1992;326:1445-1450.
Asano Y, Yoshikawa T, Suga S.  et al.  Viremia and neutralizing antibody response in infants with exanthem subitum.  J Pediatr.1989;114:535-539.
Mayama S, Cuevas LE, Sheldon J.  et al.  Prevalence and transmission of Kaposi's sarcoma-associated herpesvirus (human herpesvirus 8) in Ugandan children and adolescents.  Int J Cancer.1998;77:817-820.
Calabro ML, Gasperini P, Fiore JR, Barberiato M, Angarano G, Chieco-Bianchi L. Intrafamilial transmission of human herpesvirus 8.  J Natl Cancer Inst.2001;93:154-156.
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