RNA modifications and cancer (16)
Ferroptosis and cancer prognosis (10)
Epigenetics and DNA Methylation (9)
Cancer-related molecular mechanisms research (7)
Pain Mechanisms and Treatments (6)
Periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis syndrome (PFAPA) is characterized by recurrent febrile episodes associated with one or more of the symptoms described by the acronym, and easily misdiagnosed as other infectious diseases, especially tonsillitis. We aimed to describe the clinical, laboratory parameters and cytokine profiles in patients with PFAPA and to explore indicators to distinguish children with PFAPA from bacterial infection. Patients with PFAPA and bacterial infection, who had cytokine panels performed by Flowcytomix technique during the febrile episodes (prior to any treatments), were retrospectively enrolled from January 2020 to June 2024 in Shenzhen Children's Hospital. Clinical data were collected from inpatient medical records. Serum levels of cytokines and other laboratory parameters were compared between patients with PFAPA and those with identified bacterial infection. Multivariate regression analysis and a receiver operating characteristic (ROC) curve analysis were performed to construct a diagnostic model to assess the potential role of serum cytokines and laboratory parameters in the diagnosis of PFAPA. 67 patients with PFAPA and 160 patients with identified bacterial infection were included in this study. The level of serum IFN-γ, and the IFN-γ/IL-6 ratio in PFAPA patients were significantly higher than those in identified bacterial infection ( < 0.0001). The cutoff value of serum IFN-γ/IL-6 ratio for differentiating PFAPA from bacterial infection was > 0.43, and the area under the receiver operating characteristic curve (AUC) was 0.79, with a sensitivity of 70.15% and a specificity of 71.88%. A diagnosis model combined IL-10, platelet and IFN-γ/IL-6 ratio was built, and the AUC was 0.95, with the sensitivity and specificity as 90.3% and 89.6%, respectively. The IFN-γ/IL-6 ratio during febrile episodes may be useful in the early diagnosis of PFAPA by differentiating this disease from bacterial infection. The combined model based on IFN-γ/IL-6, IL-10, and PLT optimizes the diagnosis efficiency.
The pathogeneses of recurrent fever are quite complicated when excluding repeated infections. Recurrent fever is a common symptom for autoinflammatory diseases, relapse of Systemic-onset juvenile idiopathic arthritis (SoJIA) and recurrent Kawasaki disease (KD). There are no specific diagnostic laboratory tests for the diseases. Some studies showed that KD was the precursor of hemophagocytic lymphohistiocytosis (HLH). Macrophage activation syndrome (MAS) is another form of HLH in SoJIA. Cytokine disturbances are considered to be involved in the pathogenesis of the diseases. We describe a Chinese female toddler that developed three separate fever episodes with eventual diagnose of SoJIA within about 10 months. The first episode was diagnosed as IKD, immunoglobulin nonresponsive KD, and HLH. The second and third episodes were diagnosed as IKD and SoJIA, respectively. The fever was hard to be relieved by antipyretics, and the peak axillary temperature was above 40°C. For every fever episode, infections were excluded. For the first episode, trends over time of hemoglobin, platelets, fibrinogen, and triglycerides indicated HLH, which was finally diagnosed and treated according to the HLH-2004 protocol. For the second episode 6 months later, after excluding an HLH relapse and infections, IKD was finally diagnosed. Oral aspirin was administered, and the HLH treatment was ceased. The third episode occurred 3 months later, and SoJIA was finally diagnosed. For each episode, except for relative tests, we only tested for cytokines interleukin-1β, interleukin-6, and interferon-γ, due to limited laboratory test availability. These cytokines were elevated during remission and rose much higher in the fever phases. The case showed the difficulty to differentiating the recurrent fever in clinical practice. Surveillance of routine laboratory parameters over time might reveal a trend that indicates possible disease, even when parameter values do not meet diagnostic criteria. Changes in cytokine profiles are promising markers for differentiating recurrent fever diseases in future. An unknown immunological defect for the case may contribute to the recurrent immunological insults, and we are following up the recurrence of fever episode.
Zhonghua er ke za zhi = Chinese journal of pediatrics •
To investigate the clinical, inflammatory and genetic characteristics of cases with periodic fever, aphthous stomatitis, pharyngitis and adenitis (PFAPA) syndrome. Clinical and inflammatory manifestations and gene sequencing of 11 cases with PFAPA were retrospectively analyzed. Inflammatory markers including white blood cell (WBC) , C reactive protein (CRP) , and serum amyloid A (SAA) were compared between febrile period and intermittent period. Fifteen normal children were taken as healthy controls. The levels of plasma inflammatory cytokines including interleukin(IL)1β, IL-6, IL-17, tumor necrosis factor(TNF)-α, interferon (IFN)-γ, and granulocyte-colony stimulating factor(G-CSF) were compared between febrile period and intermittent period with paired-sample test, and compared between febrile cases and healthy controls with independent test. A total of 11 cases (7 females and 4 males) were included. The median onset age was 24 (3-60) months, and the median age of diagnosis was 69 (11-151) months. The median febrile duration was 4 (1-8) days, and the intermittent period lasted 1 to 8 weeks. All the cases had periodic fever and pharyngitis/tonsillitis, 7 of whom had combined lymphadenitis, and 5 of whom suffered from oral ulcers. Compared to intermittent-period-status,WBC ((14.7±4.1) ×10(9)/L (8.4±1.9) ×10(9)/L, 0.05), CRP((24.2±21.1) (3.3±2.1)mg/L, 0.05), SAA ((136.4±47.7) (7.1±1.1)mg/L, 0.05) were significantly elevated in febrile period. Compared to intermittent-period-status and healthy controls, plasma levels of IL-6 ((38±10) (8±4) and (8±5)ng/L, 6.514 and 6.830 respectively, 0.05), IFN-γ ((132±43) (49±21) and (53±21)ng/L, 4.069 and 4.276 respectively, 0.05), G-CSF ((403±12) (175±90) and (121±49)ng/L, 4.219 and 9.047 respectively, 0.05) were significantly higher in febrile period, while no differences were found in levels of IL-1β, IL-17 and TNF-α. Gene sequencing found MEFV gene heterozygous variation in 8 cases. PFAPA often manifests as periodic fever, pharyngitis, tonsillitis, aphthous stomatitis and adenitis. Gene sequencing analysis, detection of inflammation markers and cytokines could help with the diagnose of this disease.