Dicle ŞENER OKUR, Ümran POTA, Olcay GÜNGÖR, Sedef Zeliha ÖNER

Beyin omurilik sıvısında Human Herpes Virus-6 ve/veya Human Herpes Virus-7 saptanan çocuk hastaların değerlendirilmesi-tek merkez deneyimi

Giriş: Ekzantem subitum'un etiyolojik ajanı Human Herpes Virus-6, bebeklik döneminde ateşli nöbetlerin yaygın bir nedenidir ve bu yaş grubunda menenjit ile ilişkilendirilmiştir. Human Herpes Virus-7’de çocuklarda ekzantem subitum ve ateşli nöbetlerle ilişkili olup menenjite de neden olabilir. Human Herpes Virus-6 ve Human Herpes Virus-7'nin merkezi sinir sistemi hastalıklarındaki rolü ve sıklığı belirsizdir ve devam eden bir araştırma alanıdır. Çalışmamızda Human Herpes Virus-6 ve Human Herpes Virus-7 etkenlerinin çocukluk çağı merkezi sinir sistemi enfeksiyonlarındaki etkileri konusunda literatüre katkı sağlanması amaçlanmıştır. Gereç ve yöntem: Çalışmamıza Mart 2021-Mart 2022 tarihlerinde, merkezi sinir sistemi enfeksiyonu öntanıları ile yatırılan, beyin omurilik sıvılarında polimeraz zincir reaksiyonu ile Human Herpes Virus-6, Human Herpes Virus-7 saptanan çocuk hastalar alındı. Çalışmaya dahil edilen hastaların epidemiyolojik, klinik, laboratuvar bulguları, tedavileri ve prognozları incelendi. Bulgular: Çalışmamızda toplam 86 çocuk merkezi sinir sistemi enfeksiyonu öntanıları ile yatırıldı. Merkezi sinir sistemi enfeksiyonu öntanısı ile yatırılan çocuklardan 12’sinde (%13,9) beyin omurilik sıvısında polimeraz zincir reaksiyonu ile Human Herpes Virus-6 ve/veya Human Herpes Virus-7 saptandı. Hastaların 9’u (%75) iki yaş altındaydı. Nöbet Human Herpes Virus-6 ile enfekte olanların tümünde, Human Herpes Virus-7 ile enfekte olanların 4’ünde (%50) başvuru yakınmasıydı. Nöbet sıklığı Human Herpes Virus-7 grubunda daha az olmasına rağmen bu grupta nöbetlerin %75’i status idi. Kraniyal manyetik rezonans görüntüleme ile 3 hastada serebral venöz tromboz görüldü. Tromboz saptanan hastalarının tümünün Human Herpes Virus-7 ile enfekte olduğu saptandı. Sonuç: Çalışmamızdan elde edilen sonuçlar Human Herpes Virus-6 ve Human Herpes Virus-7 etkenlerinin çocukluk çağında merkezi sinir sistemi enfeksiyonları ve ağır nörolojik hastalıklar ile ilişkili olabileceğini göstermektedir. Çocuklarda Human Herpes Virus-7 ilişkili vaskulopatiler, otoimmun ve otoinflamatuar süreçler ile ilgili henüz yeterli sayıda veri bulunmamaktadır. Çalışmamız bu açıdan literatüre önemli bir katkı sağlamakta, çok merkezli ve ileriye yönelik çalışmalar yapılması gerekliliğini göstermektedir.

Anahtar Kelimeler:

Human Herpes Virus-6, Human Herpes Virus-7, menenjit, pediatri, nöbet

Evaluation of pediatric patients with Human Herpes Virus-6 and/or Human Herpes Virus-7 detected in cerebrospinal fluid: a single center experience

Background: Human Herpes Virus-6, is a common cause of febrile seizures in infancy and has been associated with meningitis in this age group. Human Herpes Virus-7, may also cause meningitis in children. The role and frequency of HHV-6 and HHV-7 in children's central nervous system diseases is unclear and an area of ongoing research. In our study, we aimed to contribute to the literature about effects of Human Herpes Virus-6 and Human Herpes Virus-7 in central nervous system infections, in children.Materials and methods: A retrospective study was conducted between March 2021 and March 2022. The study included children diagnosed with central nervous system infection and those found to have Human Herpes Virus-6 and or Human Herpes Virus-7 in their cerebrospinal fluid by multiplex real-time polymerase chain reaction. Results: In our study, 86 children were hospitalized with the diagnoses of central nervous system infection. We detected Human Herpes Virus-6 and/or Human Herpes Virus-7 in cerebrospinal fluid in 12 (13.9%) children. When the patients were grouped according to their age, 75% were under the age of 2 years. Seizure was the presenting complaint in all patients with Human Herpes Virus-6 and 50% patients with Human Herpes Virus-7. Although the frequency of seizures was lower in the Human Herpes Virus-7, 75% of the seizures in this group were status epilepticus. Cerebral venous thrombosis was observed in 3 patients. All patients with thrombosis were found to be infected with Human Herpes Virus-7.Conclusion: Our study findings show that Human Herpes Virus-6 and Human Herpes Virus-7 may be associated with central nervous system infections and severe neurological diseases in childhood. Our study makes an important contribution to the literature in this respect and shows the need for multicenter prospective studies.

Keywords:

Human Herpes Virus-6, Human Herpes Virus-7, meningitis, children, seizure,

PDF

___

[1] Michos AG, Syriopoulou VP, Hadjichristodoulou C, Daikos GL, Lagona E, Douridas P, Mostrou G, Theodoridou M. Aseptic meningitis in children: analysis of 506 cases. PLoS One. 2007; 2(7): e674
[2] Martin NG, Iro MA, Sadarangani M, Goldacre R, Pollard AJ, Goldacre MJ. Hospital admissions for viral meningitis in children in England over five decades: a population-based observational study. Lancet Infect Dis. 2016; 16(11): 1279
[3] Hviid A, Melbye M. The epidemiology of viral meningitis hospitalization in childhood Epidemiology. 2007; 18(6): 695
[4] Centers for Disease Control and Prevention (CDC). Outbreaks of aseptic meningitis associated with echoviruses 9 and 30 and preliminary surveillance reports on enterovirus activity-United States, 2003. MMWR Morb Mortal Wkly Rep. 2003; 52(32):761-764
[5] Nigrovic LE. Aseptic meningitis Handb Clin Neurol. 2013; 112: 1153
[6] Bronstein DE, Glaser CA. Aseptic meningitis and viral meningitis. In: Feigin and Cherry's textbook of pediatric infectious diseases, 8th, Cherry JD, Harrison GJ, Kaplan SL, Steinbach WJ, Hotes PJ (Eds), Elsevier, Philadelphia 2019. Vol 1, p.355
[7] Cassady K, Gnann JW, Whitley RJ. Viral infections of the central nervous system. In: Therapy of Infectious Diseases, Baddour L, Gorbach S (Eds), WB Saunders, Philadelphia 2003. p.237
[8] Abedi GR, Watson JT, Nix WA, Oberste MS, Gerber SI. Enterovirus and Parechovirus Surveillance-United States, 2014-2016. MMWR Morb Mortal Wkly Rep. 2018; 67(18): 515
[9] Rotbart HA. Viral meningitis and the aseptic meningitis syndrome. In: Infections of the Central Nervous System, 2nd ed, Scheld MW, Durack WR (Eds), Lippincott Raven, Philadelphia 1997. p.23
[10] Caserta MT, Hall CB. Human Herpes-6. In: Infections of the Central Nervous System, 2nd ed, Scheld MW, Durack WR (Eds), Lippincott Raven, Philadelphia 1997. p.129
[11] Yoshikawa T, Ihira M, Suzuki K, Suga S, Matsubara T, Furukawa S, Asano Y. Invasion by human herpesvirus 6 and human herpesvirus 7 of the central nervous system in patients with neurological signs and symptoms. Arch Dis Child. 2000; 83(2): 170-171
[12] 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(6): 619-623
[13] Ansari A, Li S, Abzug MJ, Weinberg A. Human herpesviruses 6 and 7 and central nervous system infection in children. Emerg Infect Dis. 2004; 10(8): 1450-1454
[14] Caserta MT, Hall CB, Schnabel K, McIntyre K, Long C, Costanzo M, Dewhurst S, Insel R, Epstein LG. Neuroinvasion and persistence of human herpesvirus 6 in children. J Infect Dis. 1994; 170(6): 1586-1589
[15] Kondo K, Nagafuji H, Hata A, Tomomori C, Yamanishi K. Association of human herpesvirus 6 infection of the central nervous system with recurrence of febrile convulsions. J Infect Dis. 1993;167:1197–1200
[16] Torigoe S, Koide W, Yamada M, Miyashiro E, Tanaka-Taya K, Yamanishi K: Human herpesvirus 7 infection associated with central nervous system manifestations. J ediatr 1996; 129(2): 301–305
[17] Suga S, Yoshikawa T, Asano Y, Kozawa T, Nakashima T, Kobayashi I, Yazaki T, Yamamoto H, et al. Clinical and virological analyses of 21 infants with exanthem subitum (roseola infantum) and central nervous system complications. Ann Neurol 1993; 33(6): 597–603
[18] Hall CB, Long CE, Schnabel KC, Caserta MT, McIntyre KM, Costanzo MA, Knott A, Dewhurst S et al. Human herpesvirus-6 infection in children: a prospective study of complications and reactivation. N Engl J Med. 1994; 331(7):432–438
[19] Kleines M, Scheithauer S, Schiefer J, Häusler M. Clinical application of viral cerebrospinal fluid PCR testing for diagnosis of central nervous systemdisorders: a retrospective 11-year experience. Diagn Microbiol Infect Dis. 2014; 80: 207e15
[20] Messacar K, Breazeale G, Wei Q, Robinson CC, Dominguez SR. Epidemiology and clinical characteristics of infants with human parechovirus or human herpes virus-6 detected in cerebrospinal fluid tested for enterovirus or herpes simplex. virus. J Med Virol 2015; 87: 829e35
[21] Wada K, Mizoguchi S, Ito Y, et al. Multiplex real-time PCR for the simultaneous detection of herpes simplex virus, human herpesvirus 6, and human herpesvirus 7. Microbiol Immunol. 2009; 53: 22e9
[22] Säll O, Thulin Hedberg S, Neander M, Tiwari S, Dornon L, Bom R, Lagerqvist N, Sundqvist M, Mölling P. Etiology of Central Nervous System Infections in a Rural Area of Nepal Using Molecular Approaches. Am J Trop Med Hyg. 2019; 101(1): 253-259
[23] Huang LM, Lee CY, Lee PI, Chen JM, Wang PJ. Meningitis caused by human herpesvirus-6. Arch Dis Child. 1991 Dec;66(12):1443-4.
[24] Epstein LG, Shinnar S, Hesdorffer DC, Nordli DR, Hamidullah A, Benn EK, Pellock JM, Frank LM, et al; FEBSTAT study team. Human herpesvirus 6 and 7 in febrile status epilepticus: the FEBSTAT study. Epilepsia. 2012; 53(9): 1481-1488
[25] Parisi SG, Basso M, Del Vecchio C, Andreis S, Franchin E, Bello FD, Pagni S, et al. Virological testing of cerebrospinal fluid in children aged less than 14 years with a suspected central nervous system infection: A retrospective study on 304 consecutive children from January 2012 to May 2015. Eur J Paediatr Neurol. 2016; 20(4): 588-596
[26] Schwartz KL, Richardson SE, Ward KN, Donaldson C, MacGregor D, Banwell B, Mahant S, Bitnun A. Delayed primary HHV-7 infection and neurologic disease. Pediatrics. 2014; 133(6): e1541-1547
[27] Van der Berg JS, van Zeiji JH, Rotteveel JJ, Melchers WJ, Gabreels FJ, Galama JM. Neuroinvasion by human herpesvirus type 7 in a case of exanthem subitum with severe neurologic manifestations. Neurology. 1999; 52: 1077– 1079
[28] Caserta MT, Hall CB, Schnabel K, Long CE, D’Heron N. Primary human herpesvirus 7 infection: a comparison of human herpesvirus 7 and human herpesvirus 6 infection in children. J Pediatr. 1998; 133: 386–389
[29] Teach SJ, Wallace HL, Evans MJ, Duffner PK, Hay J, Faden HS. Human herpesviruses types 6 and 7 and febrile seizures. Pediatr Neurol. 1999; 21: 699–703
[30] Pohl-Koppe A, Blay M, Jager G, Weiss M. Human herpes virus type 7 DNA in the cerebrospinal fluid of children with central nervous system diseases. Eur J Pediatr. 2001; 160: 351–358
[31] Corral Í, Sainz de la Maza S, Rodríguez M, Kawiorski MM, López-Martínez MJ, Galán JC. Molecular detection of human herpesvirus 7 DNA in cerebrospinal fluid from adult patients with neurological disorders. J Neurovirol. 2018; 24(3): 333-338
[32] Ward KN. The natural history and laboratory diagnosis of human herpesviruses-6 and -7 infections in the immunocompetent. J Clin Virol. 2005; 32:183–193
[33] 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): 1-5
[34] Torigoe S, Kumamoto T, Koide W, Taya K, Yamanishi K. Clinical manifestations associated with human herpesvirus 7 infection. Arch Dis Child. 1995; 72(6): 518-519
[35] Tunkel AR, Glaser CA, Bloch KC, Sejvar JJ, Marra CM, Roos KL, Hartman BJ, Kaplan SL,et al; Infectious Diseases Society of America. The management of encephalitis: clinical practice guidelines by the Infectious Diseases Society of America. Clin Infect Dis. 2008; ; 47(3): 303-327
[36] Hall CB, Long CE, Schnabel KC, Caserta MT, McIntyre KM, Costanzo MA, Knott A, Dewhurst S, Insel RA, Epstein LG. Human herpesvirus-6 infection in children. A prospective study of complications and reactivation. N Engl J Med. 1994; 331: 432–438
[37] Agut H, Bonnafous P, Gautheret-Dejean A. Human Herpesviruses 6A, 6B, and 7. Microbiol Spectr. 2016; 4(3): DMIH2-0007-2015
[38] Zeytinoğlu A, Erensoy S, Sertöz R, Altuğlu İ, Çiçek C, Kayın M, Şirin H, Taner Ş. Santral sinir sistemi enfeksiyonlarında viral etiyolojinin İzmir’de bir üniversite hastanesinin yedi yıllık verileri üzerinden değerlendirilmesi. Mikrobiyol Bul. 2017; 51(2): 127-135
[39] Gray PE, O’Brien TA, Wagle M, Tangye SG, Palendira U, Roscioli T, et al. Cerebral Vasculitis in X-Linked Lymphoproliferative Disease Cured by Matched Unrelated Cord Blood Transplant. J Clin Immunol. 2015; 35: 604–609
[40] Steininger J, Rossmanith R, Geier CB, Leiss-Piller A, Thonhauser L, Weiss S, Hainfellner JA, Freilinger M, Schmidt WM, Eibl MM, Wolf HM. Case Report: Meningoencephalitis With Thrombotic Occlusive Vasculopathy in a Young EBV-Naïve Boy Is Associated With a Novel SH2D1A Mutation. Front Immunol. 2021;12: 747738