SINDROMUL MARSHALL (PFAPA) CAUZĂ DE FEBRĂ PERIODICĂ LA COPIL. Marshall Syndrome (PFAPA) cause of periodic fever in children
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1 Revista de Medicină Şcolară şi Universitară, Vol IV, Nr. 3, iulie 2017 SINDROMUL MARSHALL (PFAPA) CAUZĂ DE FEBRĂ PERIODICĂ LA COPIL 1,2 Cecilia Lazea, 1,2 Călin Lazăr, 2 Alexandra Popa 1 UMF Iuliu Haţieganu Cluj-Napoca 2 Clinica Pediatrie I, spitalul Clinic de Urgență pentru Copii Cluj-Napoca Rezumat Sindromul Marshall sau PFAPA (Periodic Fever, Aphthous lesions, Pharyngitis, cervical Adenitis) include următoarele manifestări clinice: febră cu caracter recurent, adenopatie cu localizare latero-cervicală, faringită şi afte bucale. Este întâlnit cu precădere la copiii preșcolari, fiind cea mai frecventă cauză de febră periodică la această vârstă. Pacienții sunt asimptomatici între episoadele febrile, iar creșterea și dezvoltarea sunt neafectate. Diagnosticul este clinic, prin excluderea altor cauze de febră periodică la copil. Examinările de laborator sunt nespecifice şi constau în reactanți de fază acută pozitivi) proteina C-reactivă cu valori crescute, leucocitoză). Tratamentul include administrarea orală de corticosteroizi şi amigdalectomia. Cuvinte cheie: febră periodică, stomatită, adenopatii, faringită, copil Marshall Syndrome (PFAPA) cause of periodic fever in children Abstract Marshall syndome or PFAPA (Periodic Fever, Aphthous lesions, Pharyngitis, cervical Adenitis) is a periodic fever syndrome including recurrent episodes of high fever, cervical adenitis, pharyngitis and aphthous stomatitis which is diagnosed in children. This disease is the most frequent cause of periodic fever in children. The patients have no clinical symptoms between episodes and the neurological and physical development is normal. Diagnosis is based on clinical criteria and laboratory parameters are unspecific. Treatment includes oral corticosteroids and tonsillectomy. Key words: periodic fever, aphthous stomatitis, adenitis, pharyngitis * Autor corespondent: Cecilia Lazea, Clinica Pediatrie I, str.moţilor nr.68, Cluj-Napoca, tel , , cecilialazea@umfcluj.ro; cicilazearo@yahoo.com Articol primit în , acceptat: , publicat: Citare: Lazea C, Lazăr C, Popa A. Marshall Syndrome (PFAPA) cause of periodic fever in children. Journal of School and University Medicine 2017;4(3):
2 Revista de medicină școlară și universitară Sindromul Marshall sau PFAPA aparține grupului de boli autoinflamatorii cu apariție în copilărie, a fost descris în anul 1987 de către Marshall şi colab. și constă în repetate episoade febrile asociate cu faringită, adenopatii cervicale, afte bucale și leucocitoză. Aceste manifestări apar cu precădere la copiii cu vârsta mai mică de 5 ani. Episoadele febrile se caracterizează prin valori crescute ale temperaturii ( C), apariție repetată la intervale de timp oarecum fixe, în medie între 2 și 8 săptămâni și care durează 3-6 zile. Febra este însoțită de adenopatii cu localizare latero-cervicală, faringită şi afte bucale. Frecvent sunt prezente și alte semne clinice: alterarea stării generale, cefalee, artralgii, mialgii, greţuri, vărsături, dureri abdominale, hepatosplenomegalie. Între episoadele febrile copiii sunt asimptomatici, iar dezvoltarea somatică şi neurologică nu este afectată [1-7]. Dacă în urmă cu câteva decenii, această boală era aproape necunoscută în practica pediatrică curentă din țara noastră în prezent este din ce în ce mai frecvent diagnosticată, evitându-se astfel supunerea copiilor la cure repetate și inutile de antibioterapie. În mod frecvent, până la stabilirea diagnosticului de PFAPA, majoritatea copiilor urmau mai mult de 5-6 tratamente cu antibiotice în decursul a 12 luni, episoadele fiind interpretate ca și faringite de etiologie bacteriană. De foarte multe ori, părinții copiilor sunt cei care semnalează similaritatea episoadelor febrile, Tabel 1.Criterii diagnos ce în PFAPA [2] acest fapt constituind un argument prețios pentru stabilirea diagnosticului. Etiopatogeneza acestei boli este incomplet cunoscută, fiind descrise mai multe teorii patogenetice: cea multifactorială în care se presupune interacțiunea dintre unele antigene virale sau bacteriene cu un anumit profil imunologic și cea poligenică. Unele studii au demonstrat existența unei activări permanente a citokinelor proinflamatorii care înregistrează valori crescute, în dezechilibru cu nivelul citokinelor antiinflamatorii, al căror răspuns este diminuat [4,8,9]. Condiționarea genetică a acestei boli este demonstrată de decelarea unor mutații la nivelul unor gene care determină apariția altor boli autoinflamatorii cu determinism monogenic [4, 9-11]. Cu toate că diagnosticul este eminamente clinic, examinările de laborator chiar nespecifiece sunt utile pentru excluderea altor cauze de sindrom febril și se înregistrează valori crescute ale VSH, proteinei C reactive şi leucocitelor. În timpul episoadelor febrile se mai constată reducerea numărului de eozinofile şi creşterea numărului de monocite [12]. Citokinele proinflamatorii înregistrează valori crescute chiar și între episoadele febrile [13,14]. Un marker diagnostic util este reprezentat de procalcitonină care este de obicei negativă în cursul episoadelor febrile [15-18]. Criteriile diagnostice au fost formulate de Thomas şi colab. în 1999 (tabelul 1). Febră recurentă cu debut sub vârsta de 5 ani, plus cel puţin unul din următoarele semne clinice: stomatită aftoasă faringită adenopatie cervicală Absenţa completă a simptomelor între pusee Creştere şi dezvoltare normală Excluderea infecțiilor respiratorii și a neutropeniei ciclice Diagnosticul diferențial se impune a fi efectuat cu alte boli autoinflamatorii care au ca și principal simptom febra periodică (tabelul 2). 30
3 Articole științifice PFAPA Tabel 2. Caracteris cile clinice ale principalelor boli autoinflamatorii monogenice la copil [3,14] Febra mediteraneană familială Deficitul de mevalonat-kinază TRAPS Hiper IgD Criopirinopatii: FCAS sindromul Muckle-Wells sindromul CINCA (NOMID) Vârsta la debut <5 ani <20 ani <1 an <20 ani <5 ani Variabil (nou-născut, adult tânăr) Tablou clinic adenopatii faringită afte bucale serozită adenopatii dureri abdominale rash cutanat dureri musculare serozită rash cutanat edem periorbitar conjunctivită adenopatie cervicală cefalee dureri abdominale vărsături diaree rash urticarian care apare după expunerea la frig meningită cronică aseptică retard somatic Durata febrei Interval de apariţie a febrei 3-6 zile 2-8 săptămâni Tratament Prednison tonsilectomie 1-3 zile luni Colchicină 3-7 zile 4-6 săptămâni 1-2 săptămâni săptămâni-luni 4-6 zile 4-6 săptămâni zile variabil corticosteroizi TNF AINS Prednison TNF corticosteroizi TNF AINS evitarea expunerii la frig dismorfism facial * TRAPS = Tumor necrosis factor receptor-associated periodic syndrome; FCAS = Familial cold autoinflammatory syndrome; NOMID = Neonatal onset multisystem inflammatory disease. Tratamentul vizează în principal febra, însă antipireticele uzuale (acetaminofen, antiinflamatoare nonsteroidiene) au efect redus în combaterea acesteia. S-a constatat ca administrarea unei singure doze de corticosteroizi (prednison sau betametazona) p.o. la debutul febrei, conduce la dispariția acesteia în câteva ore (maxim 12-24h). Uneori, dacă o primă doză nu reușește să controleze simptomatologia, este necesară a nouă administrare la interval de 12h. Cu toate acestea, corticosteroizii cu administrare orală nu influenţează evoluţia ulterioară a bolii şi nu previn recurenţele. În unele situații s-a înregistrat reducerea intervalului dintre episoadele febrile. Dozele utilizate sunt de 0,5-1 mg/kg/doză Prednison și respectiv 0,1-0,2mg/kg/doză Betametazonă. Alte medicamente utilizate sunt: Cimetidina (datorită efectului său imunomodulator) însă cu rezultate reduse; Colchicina care poate conduce la creșterea intervalului dintre atacurile febrile, astfel încât există autori care recomandă administrarea acesteia pentru prevenirea recurențelor în special la copiii la care administrarea corticosteroizilor reduce intervalul dintre episoadele febrile; Anakinra care a fost 31
4 Revista de medicină școlară și universitară utilizată în cazuri selectate, neinfluențate de administarea corticosteroizilor și colchicinei [3,4,19,20]. O altă posibilitate terapeutică este reprezentată de amigdalectomie, însă există numeroase controverse în literatura de specialitate. În favoarea amigdalectomiei pledează mărirea intervalului dintre atacurile febrile și reducerea severității simptomatologiei sau chiar dispariția recurențelor febrile la pacienții amigdalectomizați. Împotriva amigdalectomiei pledează caracterul autolimitat al bolii și posibila reapariție a atacurilor febrile după o perioadă variabilă de absența a simptomelor sau chiar persistența acestora imediat postamigdalectomie [21-24]. În consecință, amigdalectomia este recomandată în cazul pacienților la care terapia cu corticosteroizi este ineficientă și frecvența atacurilor febrile este mare. Evoluție Boala are un caracter autolimitat, frecvența episoadelor febrile scade în timp, iar după vârsta de 9-11 ani se înregistrează dispariția acestora. Cu toate acestea, există însă cazuri descrise şi la adulţi şi cazuri cu agregare familială [5,25-30]. Bibliografie 1. Marshall GS, Edwards KM, Butler J, Lawton AR. Syndrome of periodic fever, pharyngitis, and aphtous stomatitis. J Pediatr 1987;110: Thomas KT, Feder HM, Lawton AR, Edwards KM. Periodic fever syndrome in children. J Pediatr 1999;135: Wekell P, Karlsson A, Berg S, Fasth A. Review of autoinflammatory diseases, with a special focus on periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis syndrome. Acta Paediatr 2016; 105(10): Vanoni F, Theodoropoulou K, Hofer M. PFAPA syndrome: a review on treatment and outcome. Pediatr Rheumatol Online J Jun 27;14(1):38. doi: /s Padeh S, Stoffman N, Berkun Y. Periodic Fever Accompanied by Aphthous Stomatitis, Pharyngitis and Cervical Adenitis Syndrome (PFAPA Syndrome) in Adults. IMAJ 2008;10: Berkun Y, Levy R, Hurwitz A, Meir-Harel M, Lidar M, Livneh A, Padeh S. The Familial Mediterranean Fever Gene as a Modifier of Periodic Fever, Aphthous Stomatitis, Pharyngitis, and Adenopathy Syndrome. Semin Arthritis Rheum 2011;40(5): Colotto M, Maranghi M, Durante C, Rossetti M, Renzi A, Anatra MG. PFAPA Syndrome in a Young Adult with a History of Tonsillectomy. Intern Med 2011;50: Stojanov S, Hoffmann F, Kery A, Renner ED, Hartl D, Lohse P, Huss K, Fraunberger P, Malley JD, Zellerer S, Albert MH, Belohradsky BH. Cytokine profile in PFAPA syndrome suggests continuous inflammation and reduced anti-inflammatory response. Eur Cytokine Netw 2006;17(2): Kraszewska-Glomba B, Matkowska-Kocjan A, Szenborn L. The Pathogenesis of Periodic Fever, Aphthous Stomatitis, Pharyngitis and Cervical Adenitis Syndrome: A Review of Current Research. Mediators Inflamm 2015;2015: Doi: /2015/ Dagan E, Gershoni-Baruch R, Khatib I, Mori A, Brik R. MEFV, TNF1rA, CARD15 and NLRP3 mutation analysis in PFAPA. Rheumatol Int 2010;30: Di Gioia SA, Bedoni N, von Scheven-Gete A, Vanoni F, Superti-Furga A, Hofer M, Rivolta C. Analysis of the genetic basis of periodic fever with aphthous stomatitis, pharyngitis, and cervicaladenitis (PFAPA) syndrome. Sci Rep. 2015;5: doi: /srep Brown KL, Wekell P, Osla V, Sundqvist M, Sävman K, Fasth A, Karlsson A, Berg S. Profile of blood cells and inflammatory mediators in periodic fever, aphthous stomatitis, pharyngitis and adenitis (PFAPA) syndrome. Pediatrics 2010;10(65); Available from: Forsvoll J, Oymar K. C-reactive protein in the periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis (PFAPA) syndrome. Acta Paediatrica 2007;96: Feder HM, Salazar JC. A clinical review of 105 patients with PFAPA (a periodic fever syndrome). Acta Paediatrica 2010;99: Yoshihara T, Imamura T, Yokoi K, Shibata M, Kano G, Osone S, Yagi K, Todo S, Murakami Y, Yamada Y, Yamada H, Satomura S, Ishida H. Potential use of procalcitonin concen- 32
5 Articole științifice trations as a diagnostic marker of the PFAPA syndrome. Eur J Pediatr 2007;166: Yazgan H, Keles E, Yazgan Z, Gebesce A, Demirdoven E. C-reactive protein and procalcitonin during febril attacks in PFAPA syndrome. Int J Ped Otorhinolaryngol 2012;76: Kraszewska-Głomba B, Szymańska-Toczek Z, Szenborn L. Procalcitonin and C-reactive protein-based decision tree model for distinguishing PFAPA flares from acute infections. Bosn J Basic Med Sci 2016;16: Førsvoll J, Kristoffersen EK, Øymar K. Is There a Role for Procalcitonin in the Evaluation of Children with PFAPA Syndrome? Ann Paediatr Rheum 2012;3: doi: / apr Tasher D, Stein M, Dalal I, Somekh E. Colchicine prophylaxis for frequent periodic fever, aphthous stomatitis, pharyngitis and adenitis episodes. Acta Paediatrica 2008; 97: Stojanova S, Lapidusa S, Chitkaraa P, Federc H, Salazar JC, Fleisherd TA, Brown MR, Edwards KM, Ward MM, Colbert RA, Sun HW, Wood GM, Barham BK, Jones A, Aksentijevich I, Goldbach-Mansky R, Athreya B, Barron KS, Kastner DL.. Periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA) is a disorder of innate immunity and Th1 activation responsive to IL-1 blockade. PNAS 2011;108(17): Licameli G, Jeffrey J, Luz J, Jones D, Kenna M. Effect of Adenotonsillectomy in PFAPA Syndrome. Arch Otolaryngol Head Neck Surg 2008;134(2): Pignataro L, Torretta S, Pietrogrande MC, Dellepiane RM, Pavesi P, Bossi A, Drago L, Capaccio P. Outcome of Tonsillectomy in Selected Patients with PFAPA Syndrome. Arch Otolaryngol Head Neck Surg 2009;135(6): Wong K, Finlay J, Moxham P. Role of Tonsillectomy in PFAPA Syndrome. Arch Otolaryngol Head Neck Surg 2008;134(1): Peridis S, Koudoumnakis E, Theodoridis A, Stefanaki K, Helmis G, Houlakis M. Surgical outcomes and histology findings after tonsillectomy in children with periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis syndrome. Am J Otolaryngol Head Neck Med Surg 2010;31: Rossetti G, Carobbio M, Tönz D, Hofer M. Syndrome de PFAPA: une nouvelle maladie? Paediatrica 2007;18(5): Gattorno M, Caorsi R, Meini A, Cattalini M, Federici S, Zulian F, Cortis E, Calcagno G, Tommasini A, Consolini R, Simonini G, Pelagatti MA, Baldi M, Ceccherini I, Plebani A, Frenkel J, Sormani MP, Martini A. Differentiating PFAPA Syndrome from Monogenic Periodic Fevers. Pediatrics 2009; 124:e721-e Cochard M, Clet J, Le L, Pillet P, Onrubia X, Gueron T. PFAPA syndrome is not a sporadic disease. Rheumatology 2010;49: Antón-Martín P, Ortiz Movilla R, Guillén Martín S, Allende LM, Cuesta Rubio TM, López González MF, Ramos Amador JT. PFAPA syndrome in siblings. Is there a genetic background? Eur J Pediatr 2011; Available from: Valenzuela PM, Majerson D, Tapia JL, Talesnik E. Syndrome of periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA) in siblings. Clin Rheumatol 2009; 28: Sampaio IC, Rodrigo MJ, Monteiro Marques JG. Two siblings with periodic fever, aphthous stomatitis, pharyngitis, adenitis (PFAPA) syndrome. Pediatr Infect Dis J 2009; 28:
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