Two-step diagnostic method in diagnosing periodic fever with aphtha stomatitis, pharyngitis and lymphadenitis, a practice from China

doi:10.21203/rs.3.rs-2591372/v1

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Two-step diagnostic method in diagnosing periodic fever with aphtha stomatitis, pharyngitis and lymphadenitis, a practice from China

https://doi.org/10.21203/rs.3.rs-2591372/v1

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Objective

Periodic fever with aphtha stomatitis, pharyngitis and lymphadenitis (PFAPA) is an inflammatory disease characterized by recurrent fever, which mainly affects children and has a high rate of missed diagnosis in China. This study is set to summarize the clinical features of PFAPA children and to develop a feasible diagnostic method.

Methods

Base on our previous experience, a two-step method consisting of preliminary assessment with disease recognition and subsequent verification was used when diagnosing PFAPA in children. The clinical data of the PFAPA children diagnosed from June 17, 2020 to November 3, 2022 were collected and summarized, and the two-step diagnostic method was validated according to the CARRA-PFAPA diagnostic criteria.

Results

A total of 260 children with periodic fever were included in this study, 8 of them did not meet the criteria of suspected PFAPA. Of the rest, 29 lost follow-up and 9 had no more episode during follow-up. One child was excluded from PFAPA by prednisone trial. The children diagnosed with PFAPA had recurrent fever beginning at a median age of 30 months, but diagnosis was made at 13 months later. The cycle duration was 30 days and the attack lasted 4 days. Exudative tonsillitis, oral ulcer, cervical adenitis and abdominal pain were presented in 93.6%, 51.4%, 43.9% and 33.1%, respectively. Leukocytosis and elevated C-reactive protein were presented in 88.6% and 91.2% of the children during fever episode, and all returned to normal when reexamined in the interval. Cytokines were detected in 36 cases during episodes, interleukin-6 increased in all cases, interferon-γ increased in most cases, but all returned to normal during asymptomatic interval. The height and weight of the children were lower than those of normal. 39.5% of the children had a positive family history. If criteria “normal growth and development” removed, only 15 of the 213 children diagnosed with PFAPA did not fulfill the CARRA-PFAPA criteria for less than 6 episodes at the time diagnosing, but all up to the standards in follow-up.

Conclusion

PFAPA should be considered for children with recurrent fever, especially those with tonsil exudation. The two-step diagnostic method provides the indications for corticosteroid use, and thus may be appropriate in clinical practice.

Periodic fever

PFAPA syndrome

Prednisone test

Autoinflammatory disease

Upper respiratory tract infections are the most prevalent reason for outpatients, with some cases accompanied by fever and tonsillar exudation. The classic tonsillar exudation is suppurative tonsillitis caused by Streptococcus infection. Most patients have evidence of bacterial infection, such as elevated white blood cells and high CRP. In addition, tonsillar exudation is observed in infectious mononucleosis, pharyngeal conjunctival fever, mycoplasma infection, and other nonbacterial infectious inflammations. For recurrent fever with tonsillar exudation, PFAPA syndrome should be considered. PFAPA syndrome is an inflammatory disease mainly identified in childhood and is also known as Marshall syndrome, after Marshall, who first reported it in 1987 [1]. According to literature review, PFAPA is the most frequent cause of periodic fever in children, with a 4-year-old median onset age. The main manifestations consist of recurrent fever, stomatitis, lymphadenitis, and cervical lymph node enlargement, whereas a few manifestations comprise abdominal pain, arthralgia, myalgia, headache and so on. Whether antibiotics are used or not, each cycle lasts for approximately 4–6 days, with an interval of approximately 3–5 weeks [2, 3]. It was completely normal during the intermission. However, most pediatricians in China are unaware of PFAPA, resulting in a higher rate of missed diagnosis. This study aims to collect and classify PFAPA cases at multicenter in china for more than two year and propose a diagnosis scheme appropriate for grassroots units.

2.1 Patients

Patients with periodic fever were enrolled in this study since June 17, 2020. The patients included those attending at the outpatient department of the First Affiliated Hospital, Sun Yat-sen University, and those consulting on Hao Daifu (good doctor) online, a famous medical consulting web platform in China. Since March 1, 2022, some children from Fengqing County of Yunnan Province or from Qifu Hospital of Guangdong Province were enrolled as well. Due to the COVID-19 pandemic, prednisone test was performed followed the doctor’s guidance through Wechat or Hao Daifu Online. Those who lost follow-up before completing prednisone trials were excluded. Case enrollment ended on November 3rd, 2022, but follow-up was continued.

Based on our experience in treating PFAPA for more than 10 years, we developed a diagnosing method of PFAPA (Table 1). Those who met the criteria for suspected PFAPA were included in the further diagnosing process, prednisone trial and follow-up. In the process of diagnosis, special attention should be paid to excluding those conditions that may cause periodic fever, such as infectious diseases, hematologic diseases, rheumatic diseases and tumors, etc., and diagnostic error was especially vigilant during the follow-up. Patients who met the confirmed diagnostic criteria were included in the statistical analysis of their clinical manifestations.

Table 1

Criteria for patients with suspected/confirmed PFAPA
Suspected PFAPA: (All criteria must be fulfilled). 1 ≥ 4 episodes occurring regularly, with minimum fever of 38.5°C for at least 2 days per episode. If fever cycle is less than 4 weeks, 1 week of variability would be allowed. If the cycle is more than 4 weeks, 2 weeks of variability will be allowed. 2 Should have associated pharyngitis. In the absence of pharyngitis, patient must have both aphthous stomatitis and cervical adenopathy in fever episodes. 3 No runny nose or cough when fever attacks. 4 Cyclic neutropenia should be ruled out. Confirmed PFAPA: Patients with suspected PFAPA who meet the following conditions can be diagnosed with confirmed PFAPA. 1 Should be responsive to corticosteroids: patient will be considered steroid responsive if fever resolves within 4 ~ 6 h after a single dose of prednisone (2 mg/kg, max 60 mg) or in divided doses, and without any antibiotics. At least two prednisone responsive episodes are required before diagnosis. 2 Immune deficiency, rheumatic disease, lymphoma and EBV infection, etc. should be carefully excluded during follow-up.

Table-2. Temporal data at diagnosis

	average	median	interquartile range	extremums
Age of onset (month)	37.6	30.0	13.8 ~ 60.0	0.5 ~ 156
Attack days (day)	4.1	4.0	3.0 ~ 5.0	2.5 ~ 7.0
Cycle duration (day)	27.3	30.0	21.0 ~ 30.0	15.0 ~ 60.0
Course at time of visit (month)	21.7	13.0	6.0 ~ 28.3	3.0 ~ 178.0

Table -3. Clinical manifestations at fever episodes

	n. of positive (%)	n. of recorded
Tonsil exudation	191(93.6%)	204
Aphthous ulcer	95(51.4%)	185
Lymphadenitis	68(43.9%)	155
Abdominal pain	55(33.1%)	166
Arthralgia	19(11.7%)	163
Leukocytosis	164(88.6%)	185
Elevated CRP	166(91.2%)	182

Table-4. Associated gene mutations and phenotype conformity

associated gene mutation	n. of positive	phenotype conformity*
MEFV	8	1/3
NLRP1	1	1/1
NLRP3	3	2/3
NLRP12	5	1/5
NLRC4	2	0/2
PLCG2	3	0/1
RYR1	2	0/0
MVK	1	0/1
PSM	1	0/2#
TRNT1	1	0/0
* shown as the parents carrying the same mutation (denominator) manifested recurrent fever in childhood (numerator). # both parents of a double heterozygote child were heterozygote.

All patients had blood routine and C-reactive protein (CRP) examination when fever attacked, some had reexamination in the interval. Immunology, ANA and anti-dsDNA, ant streptolysin O titer (ASO) and EBV-DNA, etc. were performed in most patients. Cytokines were analyzed in some patients during episodes and intermissions. If the fever not response to corticosteroids, gene detection would be recommended.

2.2 Clinical data collection

Days of fever lasting in each episode, the cycle duration, the concomitant performance, family history, the latest height and weight were recorded in detail, together with lab examination data. We have previously observed that the cycle duration tended to shorten gradually to be relatively stable with the prolongation of disease course. In addition, we also observed that after corticosteroids use, the next episode often came up earlier, which was consistent with the results observed abroad[4]. Therefore, the "cycle duration" in this study only enrolled those in stable course of disease and excluded those after corticosteroids use. Episode duration was not fixed in each attack, so the mean days was recorded. Those anticipatorily administrated with steroids for a history of febrile convulsion and those treated with unknown medications in individual clinic were ruled out from statistics of episode duration. Some data were lacked in the early stage of study. Subjective symptoms may be unreliable in young babies. Only those data that are considered reliable were recorded.

2.3 Growth and development assessment

Growth and development were evaluated according to the growth curve made by the Capital Institute of Pediatrics based on the data of a physical development survey of children in nine provinces/cities in 2005 [5]. The children whose height/weight were between − 1sd and + 1sd were "normal", those below − 1sd were "low", and those above + 1sd were "high".

2.4 Cytokine detection

During the attack period, inflammatory factors were identified in most face-to-face patients, and some children were reexamined during the intermittent period. The upper limit of normal value for IL-2 detection is 5.71pg/ml, the upper limit of normal value for IL-4 detection is 2.80pg/ml, the upper limit of normal value for IL-6 detection is 5.30pg/ml, and the upper limit of normal value for IL-10 detection is 4.91pg /ml, the upper limit of normal value of IL-17 detection is 20.60pg/ml, the upper limit of normal value of TNF detection is 4.60pg/ml, and the upper limit of normal value of IFN-y detection is 7.42pg/ml.

2.5 Statistical analysis

The age of disease onset, fever days and cycle duration of the children were not normally distributed, so the median and percentiles were used to describe. SPSS 20.0 software was used for statistical analysis. The height and weight deviation were tested with Chi-squared test for given probabilities. P < 0.05 was considered to be statistically different.

A total of 260 children with periodic fever were included in the study. Fifty-nine children were adopted as outpatients in the authors’ hospital and the others were online. There were 214 children enrolled in the prednisone trial, among which 1 child did not accord with PFAPA response and was confirmed as recurrent respiratory tract infection in the follow-up. Finally, a total of 213 patients were diagnosed with PFAPA and included in the analysis of clinical manifestations (Figure-1). Of the 159 children diagnosed PFAPA online, 43 were suspected by local doctors to have PFAPA or periodic fever syndrome at the time of referral. Only 3 of the 54 children diagnosed PFAPA offline had suspected periodic fever syndrome in other hospitals.

Among the 213 patients, 122 were males. A boy developed periodic fever after withdrawal of glucocorticoid, which was used for congenital epilepsy, so that the age of PFAPA onset could not be determined. Periodic fever began at an age younger than 7 years in most patients (Figure-2). Five children had sustained remission for several months to years before recrudescence. The median age when PFAPA onset was 2.5 years, but diagnosis was delayed to 13 months later (Table-2).

All patients had pharyngitis when fever attacked, and most had tonsil exudates. Oral ulcer, cervical lymph node swelling and pain, abdominal pain was also common simultaneous phenomenon (Table-3). Blood routine and CRP were detected in most of the children during episodes, most of them increased, and all returned to normal during the recovery period. Cytokine detection was also performed in 36 children during attacks, interleukin (IL)-6 was increased in all of them. Interferon-G was increased in 67.6% (23/34), and IL-10 in 23.5% (8/34). IL-2, IL-4, tumor necrotic factor-a and IL-17 were rarely elevated (0/34, 1/34, 2/34 and 1/33, respectively). All of the 9 patients who reexamined returned to normal in intermission.

The physical growth data of 193 patients were recorded. The height and weight of the children were lower than normal according to age and sex, and the weight loss was even more obvious.

Periodic fever in first-degree relatives was recorded in 39.5% (75/190) patients. Gene detection was performed in 49 patients, in 22 of whom genetic abnormalities associated with auto-inflammation had identified. Four patients had at least 2 related gene mutations. The proband's offending gene mutation is verified only in some families, depending on different labs. Nevertheless, few parents who carried the same mutation had recurrent fever in their childhood. (Table-4).

CARRA-PFAPA diagnostic criteria were used for reference in these 213 cases diagnosed by the two-step method. When the criteria “normal growth and development” was deleted, only 15 patients could not fulfil for episodes less than 6, but all up to the standard when follow-up.

Periodic fever is often considered a rare disease in east Asian populations. That's true when it comes to hereditary periodic fevers such as familial Mediterranean fever, hyperimmunoglobulin D syndrome and Muckle-Wells syndrome etc. Another type of periodic fever, PFAPA, which was thought to have no racial difference in incidence [6], is common in this region. There is no clear data on the incidence of PFAPA in China. A Norwegian population survey showed an incidence of 2.3 per 10,000 children under 5 years of age [7], while a study in the United States found that the incidence of PFAPA in siblings of normal control children was 2% [8], which is close to our estimate of a rough incidence of about 1% in China. However, the diagnosis rate of PFAPA in China is obviously much lower. Only a small part of the children had been suspected or confirmed a diagnosis of periodic fever before entering our study, and most of them had experienced a long course of disease when finally diagnosed. We believe that the main reason for missed diagnosis is that in China most doctors have not yet recognized this disease, and the diagnosis procedure still faces some problems to be solved.

Unlike hereditary recurrent fevers, which can be diagnosed by genetic testing, the diagnosis of PFAPA is primarily based on clinical presentation. As the name suggests, PFAPA is characterized by recurrent fever, aphthous stomatitis, pharyngitis tonsillitis, and cervical lymphadenitis. The periodicity of fever is undoubtedly the most fundamental characteristic of PFAPA. The cycle duration and episode duration in this study were 30 days and 4 days, respectively, which was similar to most reports [9, 10].

In addition to fever, pharyngitis is the most common manifestation of an attack in both adults and children. Tonsil exudation is uncommon in adult onset patients [11]. Whereas in this study pharyngitis with tonsil exudation is the most common symptom in these children. It is reported that even in the intermission phase, the activity of immune cells in the tonsils of PFAPA patients was different from that of the control group, as well as the bacterial flora [11, 12]. And tonsillectomy had complete resolution the attacks in most patients [4, 13, 14]. The tonsillar microenvironment seems to be an important factor in the pathogenesis of PFAPA. Leukocytosis and CRP elevation are frequently seen during attacks in most patients, which tends to mislead to bacterial infection.

Although the onset of PFAPA is more frequent in younger children, onset in school-ages and even in adults have also been reported [11, 15]. We also accepted patients with adult onset (not included in this study). Some patients had experienced a long remission period in disease evolution [4, 15]. It is reasonable to remove the age limit of onset < 5 years.

Most researchers believe that the growth and development of children with PFAPA are not affected [16–18]. whereas we observed abnormal growth indexes in children with PFAPA compared with normal children of the same age and sex. The growth failure may be due to long-term recurrently uncomfortable, unnecessary antibiotic use and inadequate nutritional intake derived from the practice of light diet during fever, which is very popular in China. Growth and development were not included in this two-step diagnostic criteria because other types of periodic fever do not affect growth and development within a short period from onset, and children with delayed growth and development cannot exclude the possibility of suffering from PFAPA.

The pathogenesis of PFAPA is not yet fully understood. No single pathogenic gene mutation has been identified to independently account for PFAPA. Genetic detection has never been used as a diagnostic element for PFAPA in the accepted diagnostic criteria. Although more than one-third of the first-degree relatives ever has periodic fever and almost half of children identify genetic abnormalities associated with auto-inflammation, phenotype conformity of the parents carrying the same mutations cannot be established. We agree that PFAPA is genetically predisposed but not inherited, and that PFAPA may be caused by the combination of various degree of genetic penetrance and environmental factors [10, 19, 20].

In all current PFAPA diagnostic criteria, response to steroids is one of the key elements [21]. Fever with leukocytosis and elevated CRP always reveals a picture of bacterial infection. In this case, treatment with corticosteroids alone are obviously a concern. In the two-step diagnostic method, indications for glucocorticoid use are established once suspected PFAPA is diagnosed. When using prednisone to abort an attack, we observed that smaller doses often resulted in recurrent fever requiring a second dose. To avoid misjudgment, in diagnosing stage, we recommend a single sufficient dose of prednisone.

In general, four episodes are sufficient to describe the characteristics of periodicity. The fourth or last episode, and the next, are launched for prednisone trial. In this study the vast majority of patients who met the proposed criteria were diagnosed with PFAPA after prednisone tests, except for one child. The CARRA-PFAPA criteria is a good diagnostic method, which includes: ① recurrent fever, ② more than 6 episodes occurring with regularity, ③ normal growth and development, ④ good response to steroid, ⑤ excluding other known autoimmune/autoinflammatory disorder, cyclic neutropenia, malignancy, infection, etc [17]. We used the CARRA-PFAPA diagnostic criteria to verify our two-step method. Most of patients met the CARRA-PFAPA criteria when the criteria “normal growth and development” were eliminated. Those who had only 5 episodes when diagnosing finally fulfilled the CARRA-PFAPA criteria in follow-up. The effectiveness of different diagnostic criteria varied and led to the concept of undifferentiated periodic/recurrent fever [18, 22, 23]. Dosage of steroid or growth development may contribute to the difference between our method and others.

In this study, we found that manifestations of PFAPA children in China was somewhat different from that reported abroad. The two-step diagnostic method provides the indication of prednisone use and is feasible for primary pediatricians. Although PFAPA is a benign disease, its repeated attacks still cause trouble to the children, their families and the national health insurance system [24–26]. Therefore, it is necessary to develop a diagnostic method suitable for local condition and raise awareness of PFAPA among primary health care professionals.

PFAPA syndrome should be considered in children with periodic recurrent fever, especially those with tonsillar exudation. The two-step diagnostic scheme is appropriate and applicable in clinical practice.

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Ethics declarations

Ethics approval and consent to participate

The study was approved by the Research Ethics Board of the First Affiliated Hospital, Sun Yat-sen University; People’s Hospital of Fengqing County, Lincang City, Yunnan Province, China; Fengqing County Traditional Chinese Medicine Hospital, Lincang City, Yunnan Province, China; Clifford Hospital, Guangzhou City, China. All participants gave their informed consent to participate.

Consent for publication

All authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work. Manuscript is not under publication or consideration for publication elsewhere.

Availability of data and materials

All data generated or analyzed during this study are included in this published article and its supplementary information files.

Competing interests

The authors declare that they have no competing interests.

Funding

No funding resources for this work.

Authors’ contributions

LC and CJZ designed the study, drafted the initial manuscript. HZ, JH and TSY designed the data collection instruments and collected data. AYF, ZWK and LY analyzed the patient data. KZY contributed to the final version of the manuscript. All authors read and approved the final manuscript.

Acknowledgements

None.

Marshall GS, Edwards KM, Butler J, Lawton AR. Syndrome of periodic fever, pharyngitis, and aphthous stomatitis. J Pediatr. 1987;110(1):43-6. Epub 1987/01/01. doi: 10.1016/s0022-3476(87)80285-8. PubMed PMID: 3794885.
Hofer M, Pillet P, Cochard MM, Berg S, Krol P, Kone-Paut I, et al. International periodic fever, aphthous stomatitis, pharyngitis, cervical adenitis syndrome cohort: description of distinct phenotypes in 301 patients. Rheumatology (Oxford). 2014;53(6):1125-9. Epub 2014/02/08. doi: 10.1093/rheumatology/ket460. PubMed PMID: 24505122.
Sag E, Bilginer Y, Ozen S. Autoinflammatory Diseases with Periodic Fevers. Curr Rheumatol Rep. 2017;19(7):41. Epub 2017/06/21. doi: 10.1007/s11926-017-0670-8. PubMed PMID: 28631068.
Tasher D, Somekh E, Dalal I. PFAPA syndrome: new clinical aspects disclosed. Arch Dis Child. 2006;91(12):981-4. Epub 2006/04/06. doi: 10.1136/adc.2005.084731. PubMed PMID: 16595648; PubMed Central PMCID: PMCPMC2083007.
Li H, Ji CY, Zong XN, Zhang YQ. [Body mass index growth curves for Chinese children and adolescents aged 0 to 18 years]. Zhonghua Er Ke Za Zhi. 2009;47(7):493-8. PubMed PMID: 19951508.
M. Kliegman FS, F. Schor. Nelson textbook of pediatrics,19th ed. 2011;2011, 859.
Førsvoll J, Kristoffersen EK, Øymar 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(2):187-92. Epub 20121127. doi: 10.1111/apa.12069. PubMed PMID: 23106338.
Manthiram K, Nesbitt E, Morgan T, Edwards KM. Family History in Periodic Fever, Aphthous Stomatitis, Pharyngitis, Adenitis (PFAPA) Syndrome. Pediatrics. 2016;138(3). Epub 2016/08/28. doi: 10.1542/peds.2015-4572. PubMed PMID: 27565549; PubMed Central PMCID: PMCPMC5005017 conflicts of interest to disclose.
Vanoni F, Theodoropoulou K, Hofer M. PFAPA syndrome: a review on treatment and outcome. Pediatr Rheumatol Online J. 2016;14(1):38. Epub 2016/06/29. doi: 10.1186/s12969-016-0101-9. PubMed PMID: 27349388; PubMed Central PMCID: PMCPMC4924332.
Perko D, Debeljak M, Toplak N, Avčin T. Clinical features and genetic background of the periodic Fever syndrome with aphthous stomatitis, pharyngitis, and adenitis: a single center longitudinal study of 81 patients. Mediators Inflamm. 2015;2015:293417. Epub 2015/03/31. doi: 10.1155/2015/293417. PubMed PMID: 25821352; PubMed Central PMCID: PMCPMC4364074.
Cantarini L, Vitale A, Sicignano LL, Emmi G, Verrecchia E, Patisso I, et al. Diagnostic Criteria for Adult-Onset Periodic Fever, Aphthous Stomatitis, Pharyngitis, and Cervical Adenitis (PFAPA) Syndrome. Front Immunol. 2017;8:1018. Epub 2017/10/04. doi: 10.3389/fimmu.2017.01018. PubMed PMID: 28970828; PubMed Central PMCID: PMCPMC5609591.
Luu I, Sharma A, Guaderrama M, Peru M, Nation J, Page N, et al. Immune Dysregulation in the Tonsillar Microenvironment of Periodic Fever, Aphthous Stomatitis, Pharyngitis, Adenitis (PFAPA) Syndrome. J Clin Immunol. 2020;40(1):179-90. Epub 2019/12/07. doi: 10.1007/s10875-019-00724-2. PubMed PMID: 31807979; PubMed Central PMCID: PMCPMC7085444.
Førsvoll J, Øymar K. The role of tonsillectomy in the Periodic Fever, Aphthous stomatitis, Pharyngitis and cervical Adenitis syndrome; a literature review. BMC Ear Nose Throat Disord. 2018;18:3. Epub 2018/02/28. doi: 10.1186/s12901-017-0049-5. PubMed PMID: 29483843; PubMed Central PMCID: PMCPMC5824547.
Broderick L, Carvalho D, Magit A, Jiang W, Leuin S, Bothwell M, et al. Long-term outcomes of tonsillectomy in children with periodic fever, aphthous stomatitis, pharyngitis, adenitis (PFAPA) syndrome. Pediatr Rheumatol Online J. 2015;13(Suppl 1):O78. Epub 20150928. doi: 10.1186/1546-0096-13-s1-o78. PubMed Central PMCID: PMCPMC4597172.
Vitale A, Orlando I, Lopalco G, Emmi G, Cattalini M, Frediani B, et al. Demographic, clinical and therapeutic findings in a monocentric cohort of adult patients with suspected PFAPA syndrome. Clin Exp Rheumatol. 2016;34(6 Suppl 102):77-81. Epub 20161025. PubMed PMID: 27791949.
Thomas KT, Feder HM, Jr., Lawton AR, Edwards KM. Periodic fever syndrome in children. J Pediatr. 1999;135(1):15-21. Epub 1999/07/07. doi: 10.1016/s0022-3476(99)70321-5. PubMed PMID: 10393598.
Amarilyo G, Rothman D, Manthiram K, Edwards KM, Li SC, Marshall GS, et al. Consensus treatment plans for periodic fever, aphthous stomatitis, pharyngitis and adenitis syndrome (PFAPA): a framework to evaluate treatment responses from the childhood arthritis and rheumatology research alliance (CARRA) PFAPA work group. Pediatr Rheumatol Online J. 2020;18(1):31. Epub 2020/04/16. doi: 10.1186/s12969-020-00424-x. PubMed PMID: 32293478; PubMed Central PMCID: PMCPMC7157990.
Luu I, Nation J, Page N, Carvalho D, Magit A, Jiang W, et al. Undifferentiated recurrent fevers in pediatrics are clinically distinct from PFAPA syndrome but retain an IL-1 signature. Clin Immunol. 2021;226:108697. Epub 20210224. doi: 10.1016/j.clim.2021.108697. PubMed PMID: 33636366; PubMed Central PMCID: PMCPMC8089050.
Takeuchi Y, Shigemura T, Kobayashi N, Nagumo H, Furumoto M, Ogasawara K, et al. Clinical features and new diagnostic criteria for the syndrome of periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis. Int J Rheum Dis. 2019;22(8):1489-97. Epub 2019/05/28. doi: 10.1111/1756-185x.13610. PubMed PMID: 31131563.
Di Gioia SA, Bedoni N, von Scheven-Gête A, Vanoni F, Superti-Furga A, Hofer M, et al. Analysis of the genetic basis of periodic fever with aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome. Sci Rep. 2015;5:10200. Epub 2015/05/20. doi: 10.1038/srep10200. PubMed PMID: 25988833; PubMed Central PMCID: PMCPMC4437314.
Vanoni F, Federici S, Antón J, Barron KS, Brogan P, De Benedetti F, et al. An international delphi survey for the definition of the variables for the development of new classification criteria for periodic fever aphtous stomatitis pharingitis cervical adenitis (PFAPA). Pediatr Rheumatol Online J. 2018;16(1):27. Epub 2018/04/20. doi: 10.1186/s12969-018-0246-9. PubMed PMID: 29669569; PubMed Central PMCID: PMCPMC5907175.
Vanoni F, Caorsi R, Aeby S, Cochard M, Antón J, Berg S, et al. Towards a new set of classification criteria for PFAPA syndrome. Pediatr Rheumatol Online J. 2018;16(1):60. Epub 2018/09/23. doi: 10.1186/s12969-018-0277-2. PubMed PMID: 30241480; PubMed Central PMCID: PMCPMC6151014.
De Pauli S, Lega S, Pastore S, Grasso DL, Bianco AMR, Severini GM, et al. Neither hereditary periodic fever nor periodic fever, aphthae, pharingitis, adenitis: Undifferentiated periodic fever in a tertiary pediatric center. World J Clin Pediatr. 2018;7(1):49-55. Epub 20180208. doi: 10.5409/wjcp.v7.i1.49. PubMed PMID: 29456932; PubMed Central PMCID: PMCPMC5803565.
Costagliola G, Maiorino G, Consolini R. Periodic Fever, Aphthous Stomatitis, Pharyngitis, and Cervical Adenitis Syndrome (PFAPA): A Clinical Challenge for Primary Care Physicians and Rheumatologists. Front Pediatr. 2019;7:277. Epub 2019/07/25. doi: 10.3389/fped.2019.00277. PubMed PMID: 31334209; PubMed Central PMCID: PMCPMC6624732.
Grimwood C, Kone-Paut I, Piram M, Rossi-Semerano L, Hentgen V. Health-related quality of life in children with PFAPA syndrome. Orphanet J Rare Dis. 2018;13(1):132. Epub 20180809. doi: 10.1186/s13023-018-0878-3. PubMed PMID: 30092788; PubMed Central PMCID: PMCPMC6085641.
Sparud-Lundin C, Berg S, Fasth A, Karlsson A, Wekell P. From uncertainty to gradually managing and awaiting recovery of a periodic condition- a qualitative study of parents´ experiences of PFAPA syndrome. BMC Pediatr. 2019;19(1):99. Epub 20190408. doi: 10.1186/s12887-019-1458-y. PubMed PMID: 30961562; PubMed Central PMCID: PMCPMC6454720.

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Two-step diagnostic method in diagnosing periodic fever with aphtha stomatitis, pharyngitis and lymphadenitis, a practice from China

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Abstract

Objective

Methods

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1. Introduction

2. Materials and methods

2.1 Patients

2.2 Clinical data collection

2.3 Growth and development assessment

2.4 Cytokine detection

2.5 Statistical analysis

3. Results

4. Discussion

5. Conclusion

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