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RecruitingNCT05656365Updated Apr 8, 2026

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

An observational study in Periodic Fever, Aphthous Stomatitis, Pharyngitis, And Cervical Adenitis (Pfapa), Obstructive Sleep Apnea and Tonsillitis, sponsored by National Institute of Allergy and Infectious Diseases (NIAID). Recruiting at 3 sites in United States. Open to participants aged 1 Month to 99 Years. Per ClinicalTrials.gov, last updated 2026-04-08.

Sponsored by National Institute of Allergy and Infectious Diseases (NIAID) · Observational

From the registry’s dates

  • Started May 2023; still recruiting 3 years 5 months later.
Study type
Observational
Model
Cohort
Time perspective
Prospective
Enrollment
1,500
Ages
1 Month to 99 Years
Sex
All
01

Study 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.

Read the detailed description

Study Description:

The purpose of this multisite study is to collect specimens and data from patients with periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome and other tonsil disorders for genetic, immunologic, cellular, molecular, and microbial research into the pathogenesis of these conditions. Specimens include blood, saliva, buccal swabs, oropharyngeal swabs, nasopharyngeal swabs, nasopharyngeal wash, and/or stool. If a participant is scheduled to undergo a clinically indicated tonsillectomy and/or adenoidectomy, then leftover clinical specimens will also be collected for research. Participants may either be seen in person at the study sites or may be seen remotely via telehealth and provide send-in samples collected locally.

Primary Objective:

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

Primary Endpoints:

  1. Identify genetic risk variants for PFAPA and other tonsil disorders.
  2. 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.
  3. Characterize the tonsillar/adenoid, oral, nasal and/or stool microbiota in people with PFAPA and other tonsil disorders.
  4. Characterize clinical outcomes following tonsillectomy and other clinically indicated treatments.

Secondary Objective: To understand the characteristics and function of unique cell populations in the pharyngeal lymphoid tissues (tonsils and adenoids) and how immune responses to antigens are generated in these tissues.

Secondary Endpoints:

  1. Study responses to antigens and infection in the mucosal lymphoid tissue and peripheral blood.
  2. Characterize unique immune cell populations present in the mucosal tissue.
  3. Characterize immunologic and molecular pathways in the tissue cells.
02

Conditions studied

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

Keywords

  • Genome-Wide Association Study (Gwas)
  • Immunology
  • Autoinflammation
  • Tonsillitis
  • Obstructive Sleep Apnea
  • Sleep Disordered Breathing
  • Natural History
03

In context

Hereditary Autoinflammatory Diseases

12 studies on the registry are indexed under Hereditary Autoinflammatory Diseases; 5 are open to participants now.

Browse Hereditary Autoinflammatory Diseases studies →

Lead sponsor

National Institute of Allergy and Infectious Diseases (NIAID) is the lead sponsor of 2,446 studies on the registry; 179 are open to participants now.

Of its 405 completed or terminated interventional studies of FDA-regulated products, 302 (75%) have results posted.

Browse National Institute of Allergy and Infectious Diseases (NIAID) studies →

Counted across the registry records on this site, refreshed daily.

04

Who can participate

Ages eligible
1 Month to 99 Years
Sexes eligible
All
Accepts healthy volunteers
No
Sampling method
Non-probability sample

Study population

Patients diagnosed with PFAPA and other tonsil disorders.

Go through the criteria one by one — yes, no or not sure — and take the list to your doctor or the study team. Kept in this browser only.

Inclusion criteria

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 (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.

Exclusion criteria

EXCLUSION CRITERIA:

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.

Terms in these criteria, in plain language(1)

Underlined terms in the criteria open these too. Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.

Informed consent

Before you join, the study team explains what taking part involves — its purpose, what happens, the risks and possible benefits — and answers your questions, so you can decide freely. Consent is usually recorded on a form (the informed consent form, ICF) signed by you or, where the law allows, by someone legally authorised to decide for you.

You can keep asking questions during the study, you are told of new information that matters, and you can choose to leave at any time.

05

Study design

Observational model
Cohort
Time perspective
Prospective
Enrollment
1,500 participants (estimated)

Groups and cohorts

  • Patients

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

06

What researchers measure

Primary outcomes

  1. 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

    Time frame: Throughout study

  2. 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

    Time frame: Throughout study

  3. 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

    Time frame: Throughout study

  4. 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

    Time frame: Throughout study

Secondary outcomes

  1. Characterize immunologic and molecular pathways in the tissue cells.

    To understand the characteristics and function of unique cell populations in the pharyngeal lymphoid tissues (tonsils and adenoids) and how immune responses to antigens are generated in these tissues

    Time frame: Throughout study

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

    To understand the characteristics and function of unique cell populations in the pharyngeal lymphoid tissues(tonsils and adenoids) and how immune responses to antigens are generated in these tissues

    Time frame: Throughout study

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

    To understand the characteristics and function of unique cell populations in the pharyngeal lymphoid tissues (tonsils and adenoids) and how immune responses to antigens are generated in these tissues

    Time frame: Throughout study

07

Study locations

2 of 3 sites recruiting
  • 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
    • For more information at the NIH Clinical Center contact Office of Patient Recruitment (OPR) · Contactccopr@nih.gov · 800-411-1222
    • Mary Bowes · Contactmbowes@cc.nih.gov · (240) 408-0970
08

References and documents

Publications

  • 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. PubMed 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, 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. PubMed 32518111 ↗
  • 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. PubMed 21478439 ↗

Individual participant data

Plan to share: Yes — Deidentified IPD that underlie results in a publication or associated with genomic data deposited in a data base will be shared.

Supporting information: Study protocol, Statistical analysis plan, Informed consent form, Clinical study report, 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.

09

Timeline

Tracking since Sep 25, 2026
ElapsedEstimatedEstimated, not yet reached

Started May 2023 (actual). Primary completion is estimated for Jun 2037, 169 months after the start.

How these figures are worked out, and which studies are left out of them.

Registered
Dec 15, 2022
First posted
Dec 19, 2022
StartActual
May 23, 2023
Primary completionEst.
Jun 30, 2037
CompletionEst.
Dec 31, 2038
Last update
Apr 8, 2026
What these dates mean
Start.
When the first participant enrolled; while estimated, when the study expects to open to recruitment.
Primary completion.
When the last participant was examined or treated to collect data for the study's main question, its primary outcome. A study that stopped early gives the date its data collection stopped.
Completion.
When the last participant's last visit took place, for every outcome, secondary ones and side effects included: the end of the study. Often later than primary completion, sometimes the same day.
Actual and Est.
Actual means the registry says the date has happened. Est. (estimated) is a date the sponsor plans or expects. It can still move, and the sponsor is expected to change it to actual once it has passed.
No changes since tracking began. The registry record was last updated on Apr 8, 2026, before this site started recording changes on Sep 25, 2026. Its history is on ClinicalTrials.gov ↗
10

Registry details

Key details

Study ID
NCT05656365
Lead sponsor
National Institute of Allergy and Infectious Diseases (NIAID)
Responsible party
Sponsor
First posted
Dec 19, 2022
Start date
May 23, 2023
Primary completion
Jun 30, 2037 (estimated)
Completion
Dec 31, 2038 (estimated)
Last update
Apr 8, 2026

Study contacts

Mary T Bowes
Contact
mbowes@cc.nih.gov
(240) 408-0970
Kalpana Manthiram, M.D.
Contact
kalpana.manthiram@nih.gov
(301) 529-4787
Kalpana Manthiram, M.D.
principal investigator · National Institute of Allergy and Infectious Diseases (NIAID)

Oversight

FDA-regulated drug
No
FDA-regulated device
No
View the source record on ClinicalTrials.gov ↗

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