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Pediatric Rheumatology
Published in: Pediatric Rheumatology 1/2013

Open Access 01-12-2013 | Research

Elevated levels of CXCL10 in the Periodic Fever, Aphthous stomatitis, Pharyngitis and cervical Adenitis syndrome (PFAPA) during and between febrile episodes; an indication of a persistent activation of the innate immune system

Authors: Jostein Førsvoll, Einar Klæboe Kristoffersen, Knut Øymar

Published in: Pediatric Rheumatology | Issue 1/2013

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Abstract

Background

The Periodic Fever, Aphthous stomatitis, Pharyngitis and cervical Adenitis syndrome (PFAPA) is the most common periodic fever syndrome in childhood. Clinically, PFAPA may resemble autoinflammatory diseases, but the etiology is not fully understood.

Methods

We measured inflammatory proteins in plasma and hematologic parameters in children with PFAPA during and between febrile episodes, and in a control group with suspected bacterial pneumonia. In children with PFAPA, a first blood sample was taken within 24 hours of a febrile episode and a second sample between episodes. In children with pneumonia, the first sample was taken shortly after admission and a second sample after full recovery.

Results

A total of 22 children with PFAPA and 14 children with pneumonia were included. In children with PFAPA, levels of interleukin (IL) 6, CXCL10 and CCL4 were significantly increased during febrile episodes. The levels of IL-6 and CXCL10 were higher in children with PFAPA during febrile episodes than in children with pneumonia. The levels of CXCL10 remained higher in children with PFAPA between febrile episodes compared to children with pneumonia after recovery. Children with PFAPA had a relative eosinopenia and lymphocytopenia with reduced numbers of both CD4+ and CD8+ T cells during febrile episodes. This pattern was not observed in the children with pneumonia.

Conclusions

The results indicate an innate immune response as the initial step in PFAPA, and a subsequent adaptive response with activation and redistribution of T cells. Moreover, an activation of the innate immune system involving CXCL10 may persist between febrile episodes. CXCL10 may be a possibly clinical marker in children with PFAPA.
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Literature
1.
Marshall GS, Edwards KM, Butler J, Lawton AR: Syndrome of periodic fever, pharyngitis, and aphthous stomatitis. J Pediatr. 1987, 110: 43-46. 10.1016/S0022-3476(87)80285-8.CrossRefPubMed
2.
Thomas KT, Feder HM, Lawton AR, Edwards KM: Periodic fever syndrome in children. J Pediatr. 1999, 135: 15-21. 10.1016/S0022-3476(99)70321-5.CrossRefPubMed
3.
Lierl M: Periodic fever syndromes: a diagnostic challenge for the allergist. Allergy. 2007, 62: 1349-1358. 10.1111/j.1398-9995.2007.01534.x.CrossRefPubMed
4.
Forsvoll J, Kristoffersen EK, Oymar K: Incidence, clinical characteristics and outcome in Norwegian children with periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis syndrome; a population-based study. Acta Paediatr. 2013, 102: 187-192. 10.1111/apa.12069.CrossRefPubMed
5.
Padeh S, Brezniak N, Zemer D, Pras E, Livneh A, Langevitz P, Migdal A, Pras M, Passwell JH: Periodic fever, aphthous stomatitis, pharyngitis, and adenopathy syndrome: clinical characteristics and outcome. J Pediatr. 1999, 135: 98-101. 10.1016/S0022-3476(99)70335-5.CrossRefPubMed
6.
7.
Masters SL, Simon A, Aksentijevich I, Kastner DL: Horror autoinflammaticus: the molecular pathophysiology of autoinflammatory disease. Annu Rev Immunol. 2009, 27: 621-668. 10.1146/annurev.immunol.25.022106.141627.PubMedCentralCrossRefPubMed
8.
Brown KL, Wekell P, Osla V, Sundqvist M, Savman K, Fasth A, Karlsson A, Berg S: Profile of blood cells and inflammatory mediators in periodic fever, aphthous stomatitis, pharyngitis and adenitis (PFAPA) syndrome. BMC Pediatr. 2010, 10: 65-10.1186/1471-2431-10-65.PubMedCentralCrossRefPubMed
9.
Stojanov S, Lapidus S, Chitkara P, Feder H, Salazar JC, Fleisher 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. Proc Natl Acad Sci U S A. 2011, 108: 7148-7153. 10.1073/pnas.1103681108.PubMedCentralCrossRefPubMed
10.
Kolly L, Busso N, von Scheven-Gete A, Bagnoud N, Moix I, Holzinger D, Simon G, Ives A, Guarda G, So A, Morris MA, Hofer M: Periodic fever, aphthous stomatitis, pharyngitis, cervical adenitis syndrome is linked to dysregulated monocyte IL-1beta production. J Allergy Clin Immunol. 2013, 131: 1635-1643. 10.1016/j.jaci.2012.07.043.CrossRefPubMed
11.
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: 90-97.PubMed
12.
Forsvoll JA, Oymar K: C-reactive protein in the periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis (PFAPA) syndrome. Acta Paediatr. 2007, 96: 1670-1673. 10.1111/j.1651-2227.2007.00499.x.CrossRefPubMed
13.
Yazgan H, Keles E, Yazgan Z, Gebesce A, Demirdoven M: C-reactive protein and procalcitonin during febril attacks in PFAPA syndrome. Int J Pediatr Otorhinolaryngol. 2012, 76: 1145-1147. 10.1016/j.ijporl.2012.04.022.CrossRefPubMed
14.
15.
Haraldsson A, Weemaes CM, Jonasdottir S, Olafsson O, Van De Wiel G, Goertz J, Klasen I: Serum immunoglobulinD in infants and children. Scand J Immunol. 2000, 51: 415-418. 10.1046/j.1365-3083.2000.00702.x.CrossRefPubMed
16.
Vinader V, Afarinkia K: A beginner's guide to chemokines. Future Med Chem. 2012, 4: 845-852. 10.4155/fmc.12.49.CrossRefPubMed
17.
Dufour JH, Dziejman M, Liu MT, Leung JH, Lane TE, Luster AD: IFN-gamma-inducible protein 10 (IP-10; CXCL10)-deficient mice reveal a role for IP-10 in effector T cell generation and trafficking. J Immunol. 2002, 168: 3195-3204.CrossRefPubMed
18.
Liu M, Guo S, Hibbert JM, Jain V, Singh N, Wilson NO, Stiles JK: CXCL10/IP-10 in infectious diseases pathogenesis and potential therapeutic implications. Cytokine Growth Factor Rev. 2011, 22: 121-130.PubMedCentralPubMed
19.
Rotondi M, Chiovato L: The chemokine system as a therapeutic target in autoimmune thyroid diseases: a focus on the interferon-gamma inducible chemokines and their receptor. Curr Pharm Des. 2011, 17: 3202-3216. 10.2174/138161211798157559.CrossRefPubMed
20.
Maurer M, von Stebut E: Macrophage inflammatory protein-1. Int J Biochem Cell Biol. 2004, 36: 1882-1886. 10.1016/j.biocel.2003.10.019.CrossRefPubMed
21.
Rincon M: Interleukin-6: from an inflammatory marker to a target for inflammatory diseases. Trends Immunol. 2012, 33: 571-577. 10.1016/j.it.2012.07.003.CrossRefPubMed
22.
Commins SP, Borish L, Steinke JW: Immunologic messenger molecules: cytokines, interferons, and chemokines. J Allergy Clin Immunol. 2010, 125 (Suppl 2): S53-S72.CrossRefPubMed
23.
24.
Valenzuela PM, Araya A, Perez CI, Maul X, Serrano C, Beltran C, Harris PR, Talesnik E: Profile of inflammatory mediators in tonsils of patients with periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome. Clin Rheumatol. 2013, [Epub ahead of print]
25.
Kim YH, Kim JE, Hyun MC: Cytokine response in pediatric patients with pandemic influenza H1N1 2009 virus infection and pneumonia: comparison with pediatric pneumonia without H1N1 2009 infection. Pediatr Pulmonol. 2011, 46: 1233-1239. 10.1002/ppul.21496.CrossRefPubMed
26.
Martinez FD, Stern DA, Wright AL, Taussig LM, Halonen M: Differential immune responses to acute lower respiratory illness in early life and subsequent development of persistent wheezing and asthma. J Allergy Clin Immunol. 1998, 102: 915-920. 10.1016/S0091-6749(98)70328-8.CrossRefPubMed
27.
Wibrow BA, Ho KM, Flexman JP, Keil AD, Kohrs DL: Eosinopenia as a diagnostic marker of bloodstream infection in hospitalised paediatric and adult patients: a case–control study. Anaesth Intensive Care. 2011, 39: 224-230.CrossRefPubMed
28.
Abramson JS, Givner LB, Thompson JN: Possible role of tonsillectomy and adenoidectomy in children with recurrent fever and tonsillopharyngitis. Pediatr Infect Dis J. 1989, 8: 119-120.PubMed
29.
Berlucchi M, Meini A, Plebani A, Bonvini MG, Lombardi D, Nicolai P: Update on treatment of Marshall's syndrome (PFAPA syndrome): report of five cases with review of the literature. Ann of Otol Rhinol & Laryngol. 2003, 112: 365-369.CrossRef
30.
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. 2010, 31: 472-475. 10.1016/j.amjoto.2009.06.005.CrossRefPubMed
31.
Bien E, Balcerska A: Serum soluble interleukin 2 receptor alpha in human cancer of adults and children: a review. Biomarkers. 2008, 13: 1-26. 10.1080/13547500701674063.CrossRefPubMed
32.
Lange BJ, Yang RK, Gan J, Hank JA, Sievers EL, Alonzo TA, Gerbing RB, Sondel PM: Soluble interleukin-2 receptor alpha activation in a Children's Oncology Group randomized trial of interleukin-2 therapy for pediatric acute myeloid leukemia. Pediatr Blood Cancer. 2011, 57: 398-405. 10.1002/pbc.22966.PubMedCentralCrossRefPubMed
33.
34.
Matsushita N, Kashiwagi M, Wait R, Nagayoshi R, Nakamura M, Matsuda T, Hogger P, Guyre PM, Nagase H, Matsuyama T: Elevated levels of soluble CD163 in sera and fluids from rheumatoid arthritis patients and inhibition of the shedding of CD163 by TIMP-3. Clin Exp Immunol. 2002, 130: 156-161. 10.1046/j.1365-2249.2002.01963.x.PubMedCentralCrossRefPubMed
35.
Gaini S, Pedersen SS, Koldkaer OG, Pedersen C, Moestrup SK, Moller HJ: New immunological serum markers in bacteraemia: anti-inflammatory soluble CD163, but not proinflammatory high mobility group-box 1 protein, is related to prognosis. Clin Exp Immunol. 2008, 151: 423-431. 10.1111/j.1365-2249.2007.03586.x.PubMedCentralCrossRefPubMed
36.
Schaer DJ, Schleiffenbaum B, Kurrer M, Imhof A, Bachli E, Fehr J, Moller HJ, Moestrup SK, Schaffner A: Soluble hemoglobin-haptoglobin scavenger receptor CD163 as a lineage-specific marker in the reactive hemophagocytic syndrome. Eur J Haematol. 2005, 74: 6-10. 10.1111/j.1600-0609.2004.00318.x.CrossRefPubMed
37.
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, 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-e728. 10.1542/peds.2009-0088.CrossRefPubMed
38.
Dagan E, Gershoni-Baruch R, Khatib I, Mori A, Brik R: MEFV, TNF1rA, CARD15 and NLRP3 mutation analysis in PFAPA. Rheumatol Int. 2010, 30: 633-636. 10.1007/s00296-009-1037-x.CrossRefPubMed
39.
de Jager W, Bourcier K, Rijkers GT, Prakken BJ, Seyfert-Margolis V: Prerequisites for cytokine measurements in clinical trials with multiplex immunoassays. BMC Immunol. 2009, 10: 52-10.1186/1471-2172-10-52.PubMedCentralCrossRefPubMed
Metadata
Title
Elevated levels of CXCL10 in the Periodic Fever, Aphthous stomatitis, Pharyngitis and cervical Adenitis syndrome (PFAPA) during and between febrile episodes; an indication of a persistent activation of the innate immune system
Authors
Jostein Førsvoll
Einar Klæboe Kristoffersen
Knut Øymar
Publication date
01-12-2013
Publisher
BioMed Central
Published in
Pediatric Rheumatology / Issue 1/2013
Electronic ISSN: 1546-0096
DOI
https://doi.org/10.1186/1546-0096-11-38

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