Emotional Stressors May Trigger PFAPA Attacks in Pediatric Patients


“These results show that emotional distress is associated with higher frequency of PFAPA attacks, thus may be considered as an environmental trigger for PFAPA attack," investigators stated.

Juvenile patients with Periodic Fever, Aphthous, Stomatitis, Pharyngitis, Adenitis (PFAPA) experienced a greater number of flares during the first wave of the COVID-19 pandemic. Results indicate that emotional stress may be linked to PFAPA attacks, according to a study published in Pediatric Rheumatology.1

“In March 2020, during the COVID-19 pandemic outbreak, a general lockdown was announced in Israel, closing all educational institutions and workplaces for approximately 2 months. Subsequently and on short notice (~2 weeks), preschools and schools were reopened,” investigators explained. “We assumed that familial and personal stress due to COVID-19 outbreak consequences, along with returning to school (considered a significant stressor in children) on short notice may have served as a stressful event to the patients, and therefore as a trigger for induction of flare.”

Patients from 2 large, tertiary-level Israeli medical centers with active PFAPA, aged 3-12 years, were enrolled in the study. PFAPA diagnosis was based on clinical features, repones to glucocorticoids, and the absence of other autoinflammatory manifestations. Parents were contacted via telephone during both a stressful period related to the COVID-19 pandemic restrictions (May 21-27, 2020) and a less stressful period (August 17-24, 2020) as a control. Any PFAPA attacks in the preceding 2 weeks were reported and an emotional distress scale questionnaire determined the relative stress levels within the 2 periods. The questionnaire included information about basic clinical aspects of disease, possible triggers of the patient’s attacks, and the pediatric emotional distress scale (PEDS). The aim of the study was not disclosed to participants to avoid recall bias.

Of the 99 pediatric patients ultimately enrolled in the study (mean age 7.28 years, 58.5% male), results of the emotional distress questionnaire indicated that patients had significantly higher stress levels during the more stressful period when compared with the less stressful period (35.6 ± 8.1 vs. 32.1 ±7.7, respectively, P = 0.047). Further, 38.7% (n= 41) experienced at least 1 PFAPA attack during the stressful period compared with 22.6% (n=24) in the less stressful period (p = 0.017). A statistically significant number of patients experienced more than 1 flare during the stressful period when compared with the less stressful period (14, 13.2% vs. 5, 4.7%, respectively, P = 0.04). The most common triggers reported were emotional stress (n = 46, 72.6%), as well as physical activity (n = 5), seasonal (n = 4), changes in temperature (n = 2), contact with water (n = 1), type of food (n = 1), and sun exposure (n = 1).

Investigators noted that there is a possibility that the prevalence of attacks were related to other factors that were not analyzed, such as holiday schedules and viral infections, as auto-inflammatory attacks can be triggered by common infections. Additionally, the PFAPA attacks may have influenced the emotional distress scale, instead of the opposite. However, the spread of infections decreased during the first lockdown due to social distancing and isolation. Another limitation is that the parents’ reporting of triggers, as well as identifying PFAPA attacks, may be biased based on cultural, mental, and other perceptions. Lastly, the regularity of attacks and any predictability was not assessed, which may have been helpful to identify underlying potential triggers.

“These results show that emotional distress is associated with higher frequency of PFAPA attacks, thus may be considered as an environmental trigger for PFAPA attack,” investigators concluded. “Future research is needed to confirm these findings and characterize additional triggers.”


Levinsky Y, Butbul Aviel Y, Ahmad SA, et al. PFAPA flares observed during COVID outbreak: can emotional stress trigger PFAPA attacks? A multicenter cohort study. Pediatr Rheumatol Online J. 2022;20(1):46. Published 2022 Jul 8. doi:10.1186/s12969-022-00705-7

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