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

NCT05656365 | Recruiting

• 2 other identifiers: 10001043001043-I
• Study Type: observational
• Target: 1,500
• Locations: 1 country
• Sites: 3

Brief Summary

Background: 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. Objective: To collect blood and other specimens from people with PFAPA to learn more about the illness. Eligibility: People aged 1 month or older with symptoms of PFAPA or another tonsil disorder. Design: 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. Stool. Saliva. 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.

Conditions

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

Keywords

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

Outcome Measures

Primary Outcomes (4)

• Identify genetic risk variants for PFAPA and other tonsil disorders

  To collect samples to understand the immunologic mechanisms and genetic and microbial risk factors for PFAPA and other tonsil disorders

  Throughout study

• Characterize clinical outcomes following tonsillectomy and other clinically indicated treatments.

  To collect samples to understand the immunologic mechanisms and genetic and microbial risk factors for PFAPA and other tonsil disorders

  Throughout study

• Characterize the tonsillar/adenoid, oral, nasal and/or stool microbiota in people with PFAPA and other tonsil disorders

  To collect samples to understand the immunologic mechanisms and genetic and microbial risk factors for PFAPA and other tonsil disorders

  Throughout study

• Characterize immune cell populations, gene expression including at the single cell level, epigenetic features, and protein expression ex vivo in blood, tissue, washes, or swabs from people with PFAPA and other tonsil disorders

  To collect samples to understand the immunologic mechanisms and genetic and microbial risk factors for PFAPA and other tonsil disorders

  Throughout study

Secondary Outcomes (3)

• Characterize immunologic and molecular pathways in the tissue cells.

  Throughout study

• Study responses to antigens and infection in the mucosal lymphoid tissue and peripheral blood.

  Throughout study

• Characterize unique cell populations and the immunologic and molecular pathways in the tissue cells

  Throughout study

Study Arms (1)

Patients

Patients with periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome and other tonsil disorders.

Eligibility Criteria

• Age: 1 Month - 99 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)
• Sampling Method: Non-Probability Sample

Study Population

Patients diagnosed with PFAPA and other tonsil disorders.

You may qualify if:

• Aged \>=1 month. To be seen at the NIH CC, participants must be \>=3 years of age.
• Diagnosed with PFAPA or another tonsil disorder, or has symptoms consistent with these conditions, as determined by the investigator.
• 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).
• Willing to allow specimens and data to be stored for future research.
• Willing to allow genetic testing on their biospecimens.

You may not qualify if:

• 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.

Sponsors & Collaborators

• National Institute of Allergy and Infectious Diseases (NIAID): lead

Study Sites (3)

Children's National Medical Center

Washington D.C., District of Columbia, 20010, United States

NOT YET RECRUITING

Indiana University School of Medicine

Indianapolis, Indiana, 46290, United States

RECRUITING

National Institutes of Health Clinical Center

Bethesda, Maryland, 20892, United States

RECRUITING

Related Publications (3)

• 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 BACKGROUND

• 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, Gul A, Marshall GS, Jones OY, Chandrasekharappa SC, Stepanovskiy Y, Ferguson PJ, Schwartzberg PL, Remmers EF, Kastner DL. Common genetic susceptibility loci link PFAPA syndrome, Behcet'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 BACKGROUND

• 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 BACKGROUND

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Conditions

Hereditary Autoinflammatory Diseases; Stomatitis, Aphthous; Pharyngitis; Sleep Apnea, Obstructive; Tonsillitis; Sleep Apnea Syndromes

Condition Hierarchy (Ancestors)

Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Skin Diseases, Genetic; Skin Diseases; Skin and Connective Tissue Diseases; Stomatitis; Mouth Diseases; Stomatognathic Diseases; Respiratory Tract Infections; Infections; Pharyngeal Diseases; Respiratory Tract Diseases; Otorhinolaryngologic Diseases; Apnea; Respiration Disorders; Sleep Disorders, Intrinsic; Dyssomnias; Sleep Wake Disorders; Nervous System Diseases

Study Officials

• Kalpana Manthiram, M.D.

  National Institute of Allergy and Infectious Diseases (NIAID)

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Mary T Bowes

CONTACT

(240) 408-0970; mbowes@cc.nih.gov

Kalpana Manthiram, M.D.

CONTACT

(301) 529-4787; kalpana.manthiram@nih.gov

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: PROSPECTIVE
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 15, 2022
• First Posted: December 19, 2022
• Study Start: May 23, 2023
• Primary Completion (Estimated): June 30, 2037
• Study Completion (Estimated): December 31, 2038
• Last Updated: April 8, 2026

Record last verified: 2026-04-01

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, CSR, ANALYTIC CODE
• Time Frame: Will be shared at the time of publication or data deposition into data base.
• Access Criteria: Individual level data in dbGaP is controlled access as investigators must place a request and be approved by dbGaP. Aggregated data will be open access.

Locations

US (3)