Periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA) syndrome reactivated by the initiation of oral immunotherapy (OIT)

Abbreviations

OIT

Oral immunotherapy

PFAPA

Periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis

To the Editor,

Autoinfllamamatory syndromes are disorders characterized by recurrent episodes of systemic inflammation caused by dysregulation of the innate immune system in the absence of infection, autoimmunity, or immunodeficiency. Periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome is the most common periodic fever syndrome in children, typically presenting before 5 years of age and resolving by adolescence. ¹ , ² It is characterized by recurrent febrile episodes at regular intervals, approximately every 4 weeks, lasting 3–7 days, and associated with aphthous stomatitis, pharyngitis, and cervical adenitis. Additional symptoms such as headache, arthralgia, or abdominal pain may occur, while children remain asymptomatic between episodes. Although the etiology remains unclear, PFAPA is considered an autoinflammatory condition with both genetic and environmental influences. ³ , ⁴ , ⁵

Food allergies are increasingly prevalent and significantly impact quality of life. Oral immunotherapy (OIT), a widely used treatment, involves gradual dose escalation to induce desensitization and increase the reaction threshold to allergens. ⁶ , ⁷

We report a pediatric patient in whom initiation of OIT was associated with recurrence of previously quiescent PFAPA syndrome.

The patient was a Caucasian girl born to non‐consanguineous parents, with no known family history of hereditary periodic fever syndromes or other autoinflammatory diseases. From the age of 4 years, she experienced recurrent febrile episodes occurring approximately monthly, lasting 3–5 days, and associated with marked fatigue, pharyngitis, aphthous stomatitis, headache, and arthralgia. Growth and development were normal. There were no atypical manifestations suggestive of alternative autoinflammatory syndromes, including diarrhea, skin rash, chest pain, serositis, or persistent symptoms between episodes. Infectious causes, including recurrent upper respiratory tract infections, were not identified clinically during the recurrent episodes. Although inflammatory markers were not obtained during flares, C‐reactive protein and erythrocyte sedimentation rate were normal between episodes. The patient underwent a genetic panel (Invitae 156 genes) for hereditary autoinflammatory disorders, which did not identify any pathogenic or likely pathogenic variants. Immunological evaluation showed normal IgG, IgA, and IgM levels, adequate vaccine responses, and normal lymphocyte counts. Administration of prednisone resulted in rapid resolution of fever and associated symptoms, typically within 24 h. The patient fulfilled the modified Marshall criteria, ⁵ including recurrent febrile episodes beginning before 5 years of age, aphthous stomatitis and pharyngitis, normal growth and development, and complete wellness between episodes, supporting the diagnosis of PFAPA syndrome and consistent with the Eurofever/PRINTO classification criteria. ⁸

Colchicine prophylaxis was initiated and led to a reduction in febrile episodes, although associated symptoms persisted intermittently. By the age of 9 years, given the marked decrease in episode frequency, colchicine was discontinued.

The patient also had an atopic background, including allergic rhinitis, asthma, and food allergies to peanut and kiwi, and had previously experienced iatrogenic adrenal insufficiency, related to prolonged corticosteroid treatment prescribed for asthma management. At 11 years of age, more than 1 year after her last PFAPA episode, peanut OIT was initiated following re‐evaluation in the allergy clinic. Her peanut allergy had initially presented with urticaria and vomiting. Skin prick testing showed a wheal of 12 mm (histamine control 3 mm). Total IgE was 179 kU/L and peanut‐specific IgE was 56.8 kU/L.

The OIT protocol consisted of an initial daily dose of 5 mg of peanut protein, followed by monthly dose doubling up to 64 mg, then transition to peanut butter to reach a maintenance dose of 500 mg daily. Skin testing was repeated every 6 months.

Within 2 months of OIT initiation (at 5 mg), the patient experienced two febrile episodes with symptoms consistent with PFAPA, including malaise, pharyngitis, and adenitis. OIT was temporarily interrupted for 3 days during episodes, and nonsteroidal anti‐inflammatory drugs were used, given their relative contraindication during OIT. Treatment was resumed at half‐dose for 3 days before returning to the planned protocol.

Following OIT initiation, febrile episodes occurred approximately every 3 weeks, lasting 5–6 days, and were more severe than previously reported. After dose escalation to 1 mg, the patient experienced a prolonged episode with fever, lethargy, and lymphadenopathy lasting 6 days. OIT was then discontinued for 2 months to assess for recurrence. No episodes occurred during this interruption, supporting a temporal association between OIT and PFAPA reactivation.

OIT was subsequently resumed together with prophylactic colchicine, which was reintroduced to control PFAPA symptoms. This allowed continuation of desensitization. The patient is currently in the maintenance phase (two peanuts daily), with decreasing skin test reactivity, and has not experienced febrile episodes since restarting colchicine, aside from mild symptoms occurring approximately every 2 months (Figure 1).

FIGURE 1.

Clinical timeline of PFAPA in relation to colchicine therapy and oral immunotherapy (OIT). PFAPA began at age 4 years. Colchicine initiated at age 8 years resulted in complete remission. PFAPA relapsed after OIT initiation at age 10 years and resolved following OIT discontinuation after 4 months. Colchicine was resumed with sustained remission. OIT was successfully reintroduced at age 12 years while on colchicine, with no subsequent PFAPA recurrence.

To our knowledge, only one similar case has been reported, describing a 16‐year‐old patient with PFAPA reactivation following initiation of allergen immunotherapy for pollen allergy. ⁹ As in our case, symptoms recurred after a period of remission and improved with corticosteroids. Prophylactic colchicine allowed continuation of immunotherapy and reduced symptom frequency. Systemic reactions during OIT are well recognized and may include gastrointestinal, cutaneous, and respiratory manifestations. Fever is not considered an adverse effect of OIT, suggesting PFAPA reactivation.

The potential association between allergen immunotherapy and PFAPA reactivation is clinically relevant. PFAPA may naturally follow a relapsing–remitting course, and causality cannot be established from a single case report. Nevertheless, the close temporal association between OIT initiation and symptom recurrence, followed by symptom resolution after OIT interruption and subsequent control with colchicine during OIT reintroduction, suggests that OIT may have contributed to disease reactivation in this susceptible patient. This observation highlights that a history of PFAPA should be considered when initiating desensitization, and that clinicians should monitor for recurrence of symptoms early in treatment. In our patient, reintroduction of colchicine enabled successful continuation of OIT, suggesting a practical management strategy in selected cases.

Although PFAPA pathophysiology remains incompletely understood, environmental and immunological triggers are recognized contributors to disease flares. This case supports the hypothesis that immune stimulation associated with OIT may act as a trigger in susceptible individuals, while acknowledging that PFAPA relapse may also occur independently of OIT.

In conclusion, we report reactivation of PFAPA syndrome following initiation of peanut OIT, with symptom control achieved through colchicine prophylaxis, allowing continuation of desensitization. Awareness of this potential association may help guide management in similar clinical situations.

AUTHOR CONTRIBUTIONS

Julie Couture: Writing – review and editing; formal analysis. Amandine Pelletier: Writing – original draft; data curation; formal analysis. Louis Marois: Conceptualization; investigation; writing – review and editing; validation; supervision; formal analysis.

FUNDING INFORMATION

No funding was secured for this study.

CONFLICT OF INTEREST STATEMENT

The authors declare no conflicts of interest.

CONSENT

The consent of the patient and her parent was obtained.

Pelletier A, Couture J, Marois L. Periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA) syndrome reactivated by the initiation of oral immunotherapy (OIT). Pediatr Allergy Immunol. 2026;37:e70413. doi: 10.1111/pai.70413

DATA AVAILABILITY STATEMENT

The data that support the findings of this study are available from the corresponding author upon reasonable request.