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Protocol Details

Evaluating the Genetics and Immunology of Periodic Fever, Aphthous Stomatitis, Pharyngitis, and Cervical Adenitis (PFAPA) Syndrome and Other Tonsil Disorders

This study is currently recruiting participants.

Summary | Eligibility | Citations | Contacts




Sponsoring Institute

National Institute of Allergy and Infectious Diseases (NIAID)

Recruitment Detail

Type: Participants currently recruited/enrolled
Gender: Male & Female
Min Age: 1 mo
Max Age: 99 Years

Referral Letter Required


Population Exclusion(s)



Genome-Wide Association Study (Gwas);
Obstructive Sleep Apnea;
Sleep Disordered Breathing;
Natural History

Recruitment Keyword(s)



Periodic Fever, Aphthous Stomatitis, Pharyngitis, And Cervical Adenitis (Pfapa);
Obstructive Sleep Apnea;
Tonsil Disorder;
Sleep Disordered Breathing

Investigational Drug(s)


Investigational Device(s)




Supporting Site

National Institute of Allergy and Infectious Diseases


Periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) is the most common periodic fever syndrome of childhood. Symptoms can include swelling of the glands in the throat, mouth ulcers, and tonsillitis. Removal of the tonsils can stop the periodic flareups. But researchers do not know how PFAPA develops. In this natural history study, researchers will collect specimens and data from people with PFAPA to see what they might have in common.


To collect blood and other specimens from people with PFAPA to learn more about the illness.


People aged 1 month or older with symptoms of PFAPA or another tonsil disorder.


Participants will be screened. Their medical records will be reviewed. Researchers will ask about a family history of PFAPA.

The following specimens may be collected:

Blood. Blood will be drawn either from a needle inserted into a vein or from a prick in the finger or heel.

Mucus and cells. A stick with soft padding on the tip may be rubbed inside the nostrils or mouth.



Tissue samples may be taken if participants are having surgery to remove the tonsils or adenoids. Participants having surgery may also have a nasopharyngeal wash; salt water will be squirted into the back of the throat and then sucked back out with a syringe.

Most participants will provide specimens only once. They can do this in person at the clinic; they can also have their local health providers send specimens to the researchers. Some participants may have optional follow-up visits over 10 years.

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Participants must meet all the following inclusion criteria to be eligible for this study:

1. Aged >=1 month. To be seen at the NIH CC, participants must be >=3 years of age.

2. Diagnosed with PFAPA or another tonsil disorder, or has symptoms consistent with these conditions, as determined by the investigator.

3. Able to provide informed consent (for ages >=18 years) or has a parent or guardian who can provide informed consent on their behalf (for ages <18 years).

4. Willing to allow specimens and data to be stored for future research.

5. Willing to allow genetic testing on their biospecimens.


An individual who has any condition that, in the judgment of the investigator, may put them at undue risk or make them unsuitable for participation in the study will be excluded.

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Xu Q, Milanez-Almeida P, Martins AJ, Radtke AJ, Hoehn KB, Oguz C, Chen J, Liu C, Tang J, Grubbs G, Stein S, Ramelli S, Kabat J, Behzadpour H, Karkanitsa M, Spathies J, Kalish H, Kardava L, Kirby M, Cheung F, Preite S, Duncker PC, Kitakule MM, Romero N, Preciado D, Gitman L, Koroleva G, Smith G, Shaffer A, McBain IT, McGuire PJ, Pittaluga S, Germain RN, Apps R, Schwartz DM, Sadtler K, Moir S, Chertow DS, Kleinstein SH, Khurana S, Tsang JS, Mudd P, Schwartzberg PL, Manthiram K. Adaptive immune responses to SARS-CoV-2 persist in the pharyngeal lymphoid tissue of children. Nat Immunol. 2023 Jan;24(1):186-199. doi: 10.1038/s41590-022-01367-z. Epub 2022 Dec 19. PMID: 36536106.

Manthiram K, Preite S, Dedeoglu F, Demir S, Ozen S, Edwards KM, Lapidus S, Katz AE; Genomic Ascertainment Cohort; Feder HM Jr, Lawton M, Licameli GR, Wright PF, Le J, Barron KS, Ombrello AK, Barham B, Romeo T, Jones A, Srinivasalu H, Mudd PA, DeBiasi RL, G(SqrRoot) l A, Marshall GS, Jones OY, Chandrasekharappa SC, Stepanovskiy Y, Ferguson PJ, Schwartzberg PL, Remmers EF, Kastner DL. Common genetic susceptibility loci link PFAPA syndrome, Beh(SqrRoot)(Beta)et's disease, and recurrent aphthous stomatitis. Proc Natl Acad Sci U S A. 2020 Jun 23;117(25):14405-14411. doi: 10.1073/pnas.2002051117. Epub 2020 Jun 9. PMID: 32518111; PMCID: PMC7322016.

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 Apr 26;108(17):7148-53. doi: 10.1073/pnas.1103681108. Epub 2011 Apr 8. PMID: 21478439; PMCID: PMC3084055.

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Principal Investigator

Referral Contact

For more information:

Kalpana Manthiram, M.D.
National Institute of Allergy and Infectious Diseases (NIAID)
NIHBC 04 BG RM 228
(301) 529-4787

Mary T. Bowes
National Institute of Allergy and Infectious Diseases (NIAID)

(240) 408-0970

Office of Patient Recruitment
National Institutes of Health Clinical Center (CC)
Building 61, 10 Cloister Court
Bethesda, Maryland 20892
Toll Free: 1-800-411-1222
Local Phone: 301-451-4383
TTY: TTY Users Dial 7-1-1

Clinical Trials Number:


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