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

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.

Study Overview

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

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.

• Study Type: Observational
• Enrollment (Estimated): 1500

Contacts and Locations

• Study Contact: Name: Mary T Bowes; Phone Number: (240) 408-0970; Email: mbowes@cc.nih.gov
• Study Contact Backup: Name: Kalpana Manthiram, M.D.; Phone Number: (301) 529-4787; Email: kalpana.manthiram@nih.gov

Study Locations

• United States
  • District of Columbia
    • Washington, District of Columbia, United States, 20010
      • Not yet recruiting
      • Children's National Medical Center
      • Contact: Srinivasalu Hemalatha; Phone Number: 202-476-2800; Email: HSriniva@childrensnational.org
  • Indiana
    • Indianapolis, Indiana, United States, 46290
      • Recruiting
      • Indiana University School of Medicine
      • Contact: Rachel Lemont; Phone Number: 317-944-7260; Email: rlemont@iu.edu
      • Contact: Annette Childress; Phone Number: (317) 944-7260; Email: afoti@iu.edu
  • Maryland
    • Bethesda, Maryland, United States, 20892
      • Recruiting
      • National Institutes of Health Clinical Center
      • Contact: For more information at the NIH Clinical Center contact Office of Patient Recruitment (OPR); Phone Number: TTY dial 711 800-411-1222; Email: ccopr@nih.gov
      • Contact: Mary Bowes; Phone Number: (240) 408-0970; Email: mbowes@cc.nih.gov

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 month and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

Patients diagnosed with PFAPA and other tonsil disorders.

Description

• 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 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.

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.

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

Number of groups / cohorts

1

Cohorts and Interventions

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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
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	Throughout study
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	Throughout study
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	Throughout study

Collaborators and Investigators

• Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
• Investigators: Principal Investigator: Kalpana Manthiram, M.D., National Institute of Allergy and Infectious Diseases (NIAID)

Publications and helpful links

General Publications

• 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.
• 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.
• 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.

Helpful Links

• NIH Clinical Center Detailed Web Page

Study record dates

Study Major Dates

• Study Start (Actual): May 23, 2023
• Primary Completion (Estimated): June 30, 2037
• Study Completion (Estimated): December 31, 2038

Study Registration Dates

• First Submitted: December 15, 2022
• First Submitted That Met QC Criteria: December 16, 2022
• First Posted (Actual): December 19, 2022

Study Record Updates

• Last Update Posted (Actual): March 25, 2024
• Last Update Submitted That Met QC Criteria: March 22, 2024
• Last Verified: March 21, 2024

More Information

Terms related to this study

• Keywords: Immunology; Obstructive Sleep Apnea; Natural History; Sleep Disordered Breathing; Autoinflammation; Tonsillitis; Genome-Wide Association Study (Gwas)
• Additional Relevant MeSH Terms: Pathologic Processes; Metabolic Diseases; Nervous System Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Lymphatic Diseases; Apnea; Respiration Disorders; Sleep Disorders, Intrinsic; Dyssomnias; Sleep Wake Disorders; Genetic Diseases, Inborn; Pharyngeal Diseases; Stomatognathic Diseases; Otorhinolaryngologic Diseases; Mouth Diseases; Hereditary Autoinflammatory Diseases; Proteostasis Deficiencies; Body Temperature Changes; Sleep Apnea Syndromes; Sleep Apnea, Obstructive; Respiratory Aspiration; Amyloidosis; Fever; Stomatitis; Tonsillitis; Pharyngitis; Stomatitis, Aphthous; Familial Mediterranean Fever; Lymphadenitis
• Other Study ID Numbers: 10001043; 001043-I

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: .Deidentified IPD that underlie results in a publication or associated with genomic data deposited in a data base will be shared.
• IPD Sharing Time Frame: Will be shared at the time of publication or data deposition into data base.
• IPD Sharing 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.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; ANALYTIC_CODE; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No