Clinical features and new diagnostic criteria for the syndrome of periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis.

AIM: The syndrome of periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) is a common inflammatory disease that presents with periodic fever. We aimed to establish more specific diagnostic criteria for PFAPA based on the clinical characteristics of PFAPA patients in our directory. METHOD: The clinical, laboratory, genetic, and family history details of 257 Japanese PFAPA patients treated at our and other affiliated hospitals between April 2000 and April 2018 were analyzed along with quantitative measurements of the number of CD64 molecules on neutrophils, and the levels of serum inflammatory cytokines. The sensitivity and specificity of the criteria were calculated for several diseases. RESULTS: Because recurrent fevers were crucial findings, they were defined as the required criterion. Tonsillitis/pharyngitis with white moss were important accompanying signs. Other symptoms associated with febrile episodes were cervical lymphadenitis with tenderness, aphthous stomatitis, sore throat, vomiting, and headache but not cough. A total of 159 (62%) patients had a family history of recurrent fevers, indicating autosomal dominant inheritance. C-reactive protein levels were extremely elevated during febrile attacks but normal in attack-free periods. Serum immunoglobulin D levels were high in 72 of the 199 tested patients. Oral glucocorticoid and cimetidine were extremely effective in all and 51.6% of the patients, respectively. We defined the above as supportive criteria. These criteria were sensitive and specific enough to distinguish PFAPA from other recurrent fever diseases. Raised serum interferon-γ levels and remarkable CD64 expression on neutrophils during flare-ups were recognized, indicating they contributed to diagnosis. CONCLUSION: Our new criteria are useful for diagnosing PFAPA.

Divergent clinical outcomes of alpha-glucosidase enzyme replacement therapy in two siblings with infantile-onset Pompe disease treated in the symptomatic or pre-symptomatic state.

Pompe disease is an autosomal recessive, lysosomal glycogen storage disease caused by acid α-glucosidase deficiency. Infantile-onset Pompe disease (IOPD) is the most severe form and is characterized by cardiomyopathy, respiratory distress, hepatomegaly, and skeletal muscle weakness. Untreated, IOPD generally results in death within the first year of life. Enzyme replacement therapy (ERT) with recombinant human acid alpha glucosidase (rhGAA) has been shown to markedly improve the life expectancy of patients with IOPD. However, the efficacy of ERT in patients with IOPD is affected by the presence of symptoms and cross-reactive immunologic material (CRIM) status. We have treated two siblings with IOPD with ERT at different ages: the first was symptomatic and the second was asymptomatic. The female proband (Patient 1) was diagnosed with IOPD and initiated ERT at 4 months of age. Her younger sister (Patient 2) was diagnosed with IOPD at 10 days of age and initiated ERT at Day 12. Patient 1, now 6 years old, is alive but bedridden, and requires 24-hour invasive ventilation due to gradually progressive muscle weakness. In Patient 2, typical symptoms of IOPD, including cardiac failure, respiratory distress, progressive muscle weakness, hepatomegaly and myopathic facial features were largely absent during the first 12 months of ERT. Her cardiac function and mobility were well-maintained for the first 3 years, and she had normal motor development. However, she developed progressive hearing impairment and muscle weakness after 3 years of ERT. Both siblings have had low anti-rhGAA immunoglobulin G (IgG) antibody titers during ERT and have tolerated the treatment well. These results suggest that initiation of ERT during the pre-symptomatic period can prevent and/or attenuate the progression of IOPD, including cardiomyopathy, respiratory distress, and muscle weakness for first several years of ERT. However, to improve the long-term efficacy of ERT for IOPD, new strategies for ERT for IOPD, e.g. modifying the enzyme to enhance uptake into skeletal muscle and/or to cross the blood brain barrier (BBB), will be required.

[Concentration of Soluble CD14-Subtype (Presepsin) in Plasma of Non-Inflammatory and Septic Febrile Children].

CD14 is present in macrophage, monocyte, and granulocyte cell membranes. Its soluble fraction (soluble CD14-subtype), named presepsin (P-SEP) is present in blood in association with infections, due to phagocy- tosis of microorganisms. Increased serum concentration of P-SEP was reported in adult patients with se- vere bacterial sepsis, however, reports on pediatric patients have been limited. In order to clarify if P-SEP increases in pediatric patients with bacterial sepsis, we conducted a study of plasma P-SEP concentration in children with various febrile diseases. Eighty-eight subjects (49 males, 39 females, 18 days to 168 months after birth, mean 3.2 years old) who admitted to our hospital were enrolled. Among them, blood culture was performed for 56 children. As control, twelve afebrile, non-septic children who admitted for routine cardiac catheter examinations for con- genital heart anomaly were enrolled. Blood was withdrawn on admission. Plasma was obtained within 24 hours after blood withdrawal, stored at 4 Celsius degree until assays. P-SEP was assayed using PATHFAST(TM) chemiluminescent enzyme immunoassay system (LSI Medience Inc, Tokyo, Japan). Together with P-SEP assays, blood culture, white blood cell count, serum C-reactive protein (CRP) and procalcitonin (PCT) were assayed. Local ethic committee approved this study. P-SEP concentration ranged 195 to 866 (median 445) pg/mL in patients whose blood culture was positive on admission (n=7). On the other hand, patients with blood culture negative (n=49) remained low level, 82.1 to 770 (median 242) pg/mL(p=0.046). Control subjects (n=12) showed significantly low concentration of P-SEP (mean 160, SD 189, ranged 79.4 to 411 pg/mL) compared to those from blood culture positive children (mean 487, SD 478 pg/mL, p=0.010). Though number of samples was limited, P-SEP may possibly act as a new mark- er of febrile bacteremia even in children. More study is needed for reference intervals for children. [Original].

Markedly elevated CD64 expressions on neutrophils and monocytes are useful for diagnosis of periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome during flares.

Periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome is the most commonly encountered autoinflammatory disease in children, but its pathogenesis and diagnostic biomarkers are unknown. In this study, we examined the utility of CD64, a member of the Fcγ receptors, expressions on neutrophils and monocytes in diagnosing patients with PFAPA, along with other autoinflammatory diseases exhibiting periodic fever, and bacterial infections. Although CD64 was expressed at a similar level in the attack-free period of PFAPA and in controls, CD64 expressions on both neutrophils and monocytes were dramatically increased during attacks. Serum IFN-γ also increased in some PFAPA patients during flares, suggesting the involvement of T cell activation. Our findings demonstrate that remarkable CD64 expression during PFAPA flares serves as a potential biomarker for the diagnosis. We also suspect that IFN-γ, possibly from retention of activated T cells in peripheral tissues, increases CD64 synthesis in such cases.

[The positivity of specific IgE to salmon roe and cod roe in outpatients].

PURPOSE: To clarify the positivity of specific IgE to salmon and cod roe in outpatients. METHODS: Specific IgE were assayed using CAP RAST system in 91 pediatric outpatients. They were 47 males and 44 females, including 22 allergic, 29 infectious, 10 neurological, 8 gastrointestinal, 7 urological, 6 hematologic, 3 metabolic disease and 6 other disorders. For control, 30 sera from healthy normal adult volunteers were assayed. Additionally, sera from 653 allergic patients were also collected in our laboratory. Specific IgEs against salmon and cod meat were also assayed simultaneously. RESULTS: In 91 pediatric patients, two children were salmon roe positive and one child was cod roe positive. Three children scored class 1, borderline positive in salmon roe, and one child scored class 1 in cod roe. Other children were negative in all allergens. No positive sera were found in normal adult volunteers. Among 653 specimens in our laboratory, the positivity of specific IgE to salmon and cod roe were 25%, and 9%, respectively. Infants younger than two years old had higher ratio than older children. There was a significant correlation (r = 0.676) between the titers of IgE to salmon and cod roe. On the other hand, the titers of IgE to their meats correlated less than those to their roes. Our results support previous reports that fish roe from different species have common antigen apart from those of fish meat. CONCLUSION: Positive ratio of salmon and cod roe specific IgE were 2.2 and 1.1% in pediatric outpatients.