Serum caspase-1, ASC/PYCARD, and copeptin during PFAPA attacks and remission: a prospective paired study with microbiologically confirmed febrile controls

Periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) is diagnosed clinically, and inflammatory findings during an attack may resemble those of acute infection. We examined whether serum caspase-1, ASC/PYCARD, and copeptin change within the same child between attack and remission, and whether attack-phase levels differ from those seen in microbiologically confirmed febrile illness. We enrolled 50 children with PFAPA who provided paired attack and remission samples. Thirty-five children with microbiologically confirmed febrile illness and 26 healthy children served as comparison groups. The prespecified primary outcome was the within-child change in caspase-1, estimated on the log scale with a participant-clustered generalized estimating equation. Paired changes in ASC/PYCARD and copeptin were key secondary outcomes. Secondary models compared PFAPA attacks with febrile controls after adjustment for age, sex, fever-to-sampling interval, maximum temperature, and C-reactive protein. Median caspase-1 rose from 1.93 [1.60–2.78] ng/mL in remission to 3.96 [2.89–5.60] ng/mL during attacks (geometric mean ratio [GMR], 2.10; 95% confidence interval [CI], 1.86–2.37; P < 0.001). ASC/PYCARD and copeptin also increased (GMRs, 1.98 and 1.75; Holm-adjusted P < 0.001 for both). In adjusted comparisons with febrile controls, the corresponding GMRs were 1.21 (95% CI, 1.02–1.43; nominal P = 0.028), 1.11 (95% CI, 0.95–1.30; P = 0.189), and 1.01 (95% CI, 0.89–1.15; P = 0.842). The caspase-1 difference was no longer significant after Holm correction. Caspase-1, ASC/PYCARD, and copeptin followed a clear attack-remission pattern within children with PFAPA, but their acute concentrations overlapped considerably with those measured during confirmed infections. The small residual difference in caspase-1 was secondary and did not withstand correction for multiple testing. These phase-linked changes are biologically descriptive rather than clinically discriminatory; the study did not demonstrate incremental value beyond routine inflammatory testing and does not establish PFAPA-specific inflammasome activation.