Background: Periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis (PFAPA) syndrome has been considered as a childhood syndrome. The underlying etiology of PFAPA syndrome is unclear however, currently considered as auto-immune inflammatory disease. Recently, a few cases of adult-onset of PFAPA syndrome have been reported. However, there is no report about the successful management of pregnancy complicated with PFAPA syndrome. Case presentation: The patient was a 31-year-old woman who developed recurrent episodes of high fever associated with cervical adenitis, pharyngitis and vomiting started 9 months after a delivery. She was diagnosed with PFAPA syndrome and cimetidine 800 mg/day was initiated. Since then, these symptoms got better. Cimetidine treatment was discontinued since she became pregnant (6 weeks of pregnancy). Except one febrile episode at 8 weeks gestation, she did not develop a febrile episode during pregnancy. Peripheral blood Th1/Th2 ratio was decreased from the first trimester to the second trimester of pregnancy. Then again, the ratio was steadily elevated during the third trimester. At 38 weeks, she delivered a live born infant without any complication. Two months after delivery, she developed PFAPA syndrome again and cimetidine treatment was re-initiated. However, febrile episodes were not controlled well, and Th1/Th2 ratio was further elevated compared to pregnancy status. Colchicine 0.5 mg once a day was initiated. Symptoms were diminished and Th1/Th2 ratio was gradually decreased. Conclusion: There was no case report of pregnancy complicated with PFAPA syndrome, though there were several reports of adult-onset PFAPA cases without pregnancy. The current case may be the first case report of a successful pregnancy complicated with PFAPA. In this case, PFAPA symptoms were ameliorated during pregnancy, but reappeared after delivery. We speculate that PFAPA syndrome, a Th1 type immune disorder, might be improved due to the Th1 to Th2 shifting, which was induced by pregnancy. It is necessary to investigate further about PFAPA syndrome with pregnancy and Th1/Th2 immune responses in the future. Keywords: PFAPA, Pregnancy, Th1/Th2, Adult onset, Periodic fever, Aphthous stomatitis, Pharyngitis, Cervical adenitis * Correspondence: firstname.lastname@example.org Reproductive Medicine and Immunology, Department of Obstetrics and Gynecology, Chicago Medical School, Rosalind Franklin University of Medicine and Science, 830 West End Court, Suite 400, Vernon Hills, IL 60061, USA Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Ota et al. BMC Pregnancy and Childbirth (2018) 18:207 Page 2 of 4 Background MKD and CAPS and all were negative. Cyclic neutro- PFAPA (periodic fever, aphthous stomatitis, pharyngitis penia was excluded by serial neutrophil counts. and cervical adenitis) syndrome which was first reported Her PFAPA symptoms disappeared spontaneously in 1987, is the most common autoimmune inflammatory within 5 days without antibiotic treatment and the ele- fever disorder in childhood worldwide . It is charac- vated CRP level became normal in 10 days from the first terized by predictably periodic high fever lasting for day of fever. Finally, PFAPA syndrome was diagnosed approximately 4 days (ranges 2 to7 days) and associated according to the Padeh’s criteria, which are not restricted with at least one of three clinical symptoms, such as to the age of onset . To prevent future febrile epi- pharyngitis, cervical adenitis and aphthous stomatitis . sodes, cimetidine 400 mg twice daily was started, and The underlying etiology of the disease is still unknown, 60 mg of intravenous prednisolone was given during a and the diagnosis is made with the clinical criteria pro- febrile attack. During the subsequent febrile episodes, posed by Thomas et al. ; 1) Periodic fevers with an PFAPA symptoms were lessened. After 8 months passed, early age of onset (< 5 years of age), 2) Symptoms in the she became pregnant and quit cimetidine at the 6th absence of upper respiratory tract infection with at least week of gestation by herself. She then developed only 1 of the following clinical signs: a) aphtous stomatitis, b) one febrile episode at 8th week of gestation without any cervical lymphadenitis, c) pharyngitis, 3) Exclusive of subsequent febrile episode during pregnancy, possibly cyclic neutropenia, 4) Completely asymptomatic interval due to altered maternal immunity with advanced between episodes, 5) Normal growth and development. pregnancy. Furthermore, PFAPA is required to exclude other dis- T helper (Th)1/Th2 cell ratios were analyzed every 2~ eases of recurrent fevers in childhood, such as malignan- 6 weeks during pregnancy (Fig. 1). IFN-gamma/ IL-4 cies, autoimmune and infectious disease. Genetic producing CD3+/CD4+ T helper cell ratios were ele- variants of the innate immune system, such as familial vated during the first trimester. During the second tri- Mediterranean fever (FMF), TNF receptor-associated mester, Th1/Th2 ratios were decreased. CRP remained periodic syndrome (TRAPS), mevalonate kinase defi- in the normal ranges during entire pregnancy. Whereas ciency (MKD) and cryopyrin-associated periodic syn- Th1/Th2 ratios were increased gradually even without a dromes (CAPS) are also included as the differential febrile episode during the third trimester. At 38 weeks, diagnosis since PFAPA syndrome is currently supposed she developed a premature rupture of membrane and the pathogenesis of abnormal host immune response . delivered a normal healthy male infant, weighing 2873 g. To date, some researchers reported that adult-onset of The Apgar scores (1 and 5 min) were 9 and 10 respect- PFAPA syndrome, though PFAPA syndrome is basically ively. Two months after delivery, she developed an epi- pediatric disease and usually settles in adolescence [4, 5]. sode of high fever associated with cervical adenitis, We would like to present a case of successful preg- pharyngitis and vomiting as she did prior to pregnancy. nancy complicated with PFAPA syndrome. We believe Cimetidine was re-initiated. Th1/Th2 ratio was 25.5 (Fig. this is the first report of pregnancy complicated with 1). Febrile episodes became worse in severity and fre- PFAPA, since PFAPA primarily affects preschool-age quency and Th1/Th2 ratio was further elevated to 33.4 children  and is rarely occurred in adults . one month later. Colchicine 0.5 mg once a day was added. Th1/Th2 ratio started to decrease gradually Case presentation (Fig. 2). Currently, febrile episodes remain shorter and The patient was a healthy 31-year-old woman who had milder. an uneventful delivery of a live born infant at term 4 years ago. Nine months after the delivery, she devel- Discussion and conclusions oped recurrent episodes of high fever (39 °C) followed A case of pregnancy complicated with PFAPA syndrome by cervical adenitis, pharyngitis and vomiting. A has not been reported despite some reported adult-onset disease-free interval, which ranges 4 to 8 weeks, was ob- cases . Although the exact pathogenesis of PFAPA has served between the periodic fever episodes, and a men- yet to be elucidated, it is considered as a polygenic auto- strual cycle was not related to the onset of a febrile inflammatory disease in which a microbial trigger might episode. give rise to the activation of innate immune system and Elevated C-reactive protein (peak value of 13.9 mg/dL) recruitment of activated T cells in a susceptible host, was noticed. Other laboratory studies, including leading to Th1 driven immune responses . On the immunoglobulin levels, serum complement level, other hand, the predominant Th2-type immunity has immuno-phenotypic characterization of lymphocytes, been observed during normal pregnancy. Maternal toler- HIV, CMV and EBV serology, and antinuclear antibodies, ance toward fetal allo-antigens was explained by the pre- were negative. Genetic tests for genomic DNA from dominant Th2-type immunity during pregnancy for whole blood were conducted to exclude FMF, TRAPS, protecting the fetus from maternal Th1-immunity . Ota et al. BMC Pregnancy and Childbirth (2018) 18:207 Page 3 of 4 Fig. 1 Th1/Th2 cell ratio (IFN-γ/IL-4 T helper cell ratio) was analyzed by flow cytometric analysis. An acquisition gate was established based on CD4 staining and side scatter (SCC) which included peripheral blood mononuclear cells (left). Dot plot analysis of IFN-γ and IL-4 expressing CD4 T cells from the patient. Numbers indicate percent gated cells (right) During normal pregnancy, Th1/Th2 ratio increases tran- repeated pregnancy losses [11, 12]. In this case, Th1/Th2 siently during implantation period, and then decreases ratio was elevated during the early first trimester of after implantation is over. During the third trimester, pregnancy. However, she could succeed in pregnancy Th1/Th2 ratio increases for the preparation of partur- and deliver despite the predominant Th1-type immunity ition. Persistently increased Th1/Th2 ratios have been which is harmful to pregnancy maintenance. We specu- associated with multiple implantation failures and late that PFAPA by Th1 immune disorder might be Fig. 2 Time course plot of Th1/Th2 cell ratios (IFN-γ/IL-4 T helper cell ratio) from early pregnancy to postpartum 1 year. The white box indicates the period of cimetidine treatment and the slant bow indicates the period of colchicine treatment Ota et al. BMC Pregnancy and Childbirth (2018) 18:207 Page 4 of 4 ameliorated during the second trimester of pregnancy 6. Vigo G, Zulian F. Periodic fevers with aphthous stomatitis, pharyngitis, and adenitis (PFAPA). Autoimmun Rev. 2012;12(1):52–5. possibly due to the predominant Th2 immunity estab- 7. Padeh S, Stoffman N, Berkun Y. Periodic fever accompanied by aphthous lished during pregnancy. Furthermore, pregnancy com- stomatitis, pharyngitis and cervical adenitis syndrome (PFAPA syndrome) in plicated with PFAPA can be treated as normal perinatal adults. The Israel Medical Association journal : IMAJ. 2008;10(5):358–60. 8. Padeh S, Brezniak N, Zemer D, Pras E, Livneh A, Langevitz P, Migdal A, Pras course since symptoms are relieved by shifted Th2 im- M, Passwell JH. Periodic fever, aphthous stomatitis, pharyngitis, and munity. It is necessary to pay sufficient attention because adenopathy syndrome: clinical characteristics and outcome. J Pediatr. 1999; febrile episodes are rapidly exacerbated after parturition. 135(1):98–101. 9. Kraszewska-Glomba B, Matkowska-Kocjan A, Szenborn L. The pathogenesis Abbreviations of periodic fever, Aphthous stomatitis, pharyngitis, and cervical adenitis CAPS: Cryopyrin-associated periodic syndromes; CD: Cluster of differentiation; syndrome: a review of current research. Mediat Inflamm. 2015;2015:563876. CMV: Cytomegalovirus; CRP: C-reactive protein; DNA: Deoxyribonucleic acid; 10. Saito S, Nakashima A, Shima T, Ito M. Th1/Th2/Th17 and regulatory T-cell EBV: Ebstein-Barr virus; FMF: Familial Mediterranean fever; HIV: Human paradigm in pregnancy. Am J Reprod Immunol. 2010;63(6):601–10. immunodeficiency virus; IFN: Interferon; IL: Interleukin; MKD: Mevalonate 11. Kwak-Kim J, Park JC, Ahn HK, Kim JW, Gilman-Sachs A. Immunological kinase deficiency; PFAPA: Periodic fever, aphthous stomatitis, pharyngitis, and modes of pregnancy loss. Am J Reprod Immunol. 2010;63(6):611–23. cervical adenitis; Th1/Th2: T helper 1/T helper 2; TRAPS: TNF receptor- 12. Kwak-Kim JY, Chung-Bang HS, Ng SC, Ntrivalas EI, Mangubat CP, Beaman associated periodic syndrome KD, Beer AE, Gilman-Sachs A. Increased T helper 1 cytokine responses by circulating T cells are present in women with recurrent pregnancy losses Availability of data and materials and in infertile women with multiple implantation failures after IVF. Hum The datasets used and/or analyzed during the current study are available Reprod. 2003;18(4):767–73. from the corresponding author on reasonable request. Authors’ contributions KO designed the study, performed laboratory experiment, analyzed and interpreted the data and prepared the manuscript. JKK contributed the study design and manuscript preparation. TT and HM contributed the data collection and interpretation. All authors read and approved the final manuscript. Ethics approval and consent to participate Not applicable. Consent for publication Written informed consent for publication of the clinical details and/or clinical images was obtained from the patient. A copy of the consent form is available for review by the Editor of this journal. Competing interests The authors declare that they have no competing interests. Publisher’sNote Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Author details Department of Obstetrics and Gynecology, School of Medicine, Fukushima Medical University, 1-Hikarigaoka, Fukushima 960-1247, Japan. Fukushima Medical Center for Children and Women, School of Medicine, Fukushima Medical University, 1-Hikarigaoka, Fukushima 960-1247, Japan. Reproductive Medicine and Immunology, Department of Obstetrics and Gynecology, Chicago Medical School, Rosalind Franklin University of Medicine and Science, 830 West End Court, Suite 400, Vernon Hills, IL 60061, USA. Received: 21 February 2018 Accepted: 25 May 2018 References 1. Marshall GS, Edwards KM, Butler J, Lawton AR. Syndrome of periodic fever, pharyngitis, and aphthous stomatitis. J Pediatr. 1987;110(1):43–6. 2. Thomas KT, Feder HM Jr, Lawton AR, Edwards KM. Periodic fever syndrome in children. J Pediatr. 1999;135(1):15–21. 3. Stojanov S, Hoffmann F, Kery A, Renner ED, Hartl D, Lohse P, Huss K, Fraunberger P, Malley JD, Zellerer S, et al. Cytokine profile in PFAPA syndrome suggests continuous inflammation and reduced anti- inflammatory response. Eur Cytokine Netw. 2006;17(2):90–7. 4. Cavuoto M, Bonagura VR. Adult-onset periodic fever, aphthous stomatitis, pharyngitis, and adenitis. Allergy Asthma Immunol. 2008;100(2):170. 5. Colotto M, Maranghi M, Durante C, Rossetti M, Renzi A, Anatra MG. PFAPA syndrome in a young adult with a history of tonsillectomy. Internal medicine (Tokyo, Japan). 2011;50(3):223–5.
BMC Pregnancy and Childbirth – Springer Journals
Published: Jun 4, 2018
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