Brown KL

Children with systemic autoinflammatory diseases have multiple, mixed ethnicities that reflect regional ethnic diversity.

To evaluate the ethnic diversity of children with a systemic autoinflammatory disease (SAID) in a multi-ethnic Canadian province. Self-reported ethnicity of 149 children and adolescents with a SAID in British Columbia, Canada, was analysed for ethnic representation among individual patients, across the cohort, within particular SAIDs, and compared to provincial census data on ethnic diversity. Half of reported cases had a diagnosis of either PFAPA (23.5%) or an unclassifiable autoinflammatory syndrome (31.5%), with a monogenic SAID diagnosed in only 12.8% of cases. The majority of participants (73.1%) were mixed ethnicity with European and Asian heritage reported most frequently (57.0% and 23.0% of all responses, respectively). Ethnic diversity reflected regional diversity except for West Asian, Arabic, Jewish, and Eastern European heritage, which were over-represented in SAID patients, and Chinese descent, which was under-represented in our cohort compared to the general population of British Columbia. Results from this study show extensive multi-ethnic diversity in individual patients and across the various SAIDs inclusive of monogenic SAIDs that are frequently associated with particular ethnicities. Although not disproportionately represented, this is the first report of systemic autoinflammatory disease in Canadian children of Indigenous heritage.

Measles Lymphadenopathy in a Child With PFAPA Syndrome.

Periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome is a common cause of periodic fever in children. The pathogenesis of PFAPA is unknown but likely involves immune system dysregulation and may be initiated by an environmental trigger. Tonsillectomy resolves or improves symptoms in some patients, but the reason for this is unknown; moreover, specific abnormalities in tonsillectomy specimens from PFAPA patients have not been described. Here, we report measles virus in tonsil from a child with PFAPA. Measles-type viral cytopathic effect was discovered on histological examination of tonsillar tissue after therapeutic tonsillectomy for PFAPA. Molecular testing showed the left tonsil was positive for measles RNA by reverse transcription polymerase chain reaction (RT-PCR) while the right tonsil was inconclusive (weakly positive). Real-time RT-PCR specific for measles vaccine strain RNA (genotype A) was weakly reactive in the left tonsil tissue when tested in 3 independent replicates, but this result could not be confirmed with conventional genotyping by sequencing. The relationship and clinical significance between measles virus and PFAPA in this case is unclear but may be related to PFAPA-associated immune dysregulation. Additional investigation of measles virus in PFAPA patients would be helpful in further exploring this potential association.

Increased intracellular oxygen radical production in neutrophils during febrile episodes of periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis syndrome.

Periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome is an autoinflammatory disease of unknown etiology that primarily affects preschool-aged children. PFAPA syndrome is characterized by recurrent attacks of fever and symptoms of inflammation consistent with the disease acronym. Since autoinflammatory diseases are, by definition, mediated by cells of the innate immune system, the aim of this study was to evaluate the functional features of neutrophils, the most abundant innate immune cell in the circulation, in children with PFAPA syndrome. Blood polymorphonuclear leukocytes (PMNs), obtained from patients with PFAPA syndrome during both febrile and asymptomatic, afebrile phases of the disease, as well as from healthy children (afebrile controls) and children with fever and abdominal pain (febrile controls), were analyzed for 3 key neutrophil characteristics: 1) apoptosis (measured by annexin V/7-aminoactinomycin D staining), 2) production of reactive oxygen species (ROS) (measured by luminol/isoluminol-amplified chemiluminescence), and 3) priming status (measured as responsiveness to galectin-3 and up-regulation of CD11b). Compared to PMNs obtained from patients with PFAPA syndrome during an afebrile interval and those from febrile controls, PMNs obtained from patients during a PFAPA syndrome flare produced elevated levels of intracellular NADPH oxidase-derived ROS, had significantly diminished rates of spontaneous apoptosis, and displayed signatures of priming. In contrast, PMNs from afebrile patients with PFAPA syndrome had a significantly elevated rate of spontaneous apoptosis compared to PMNs from afebrile controls. These findings demonstrate that 3 key aspects of neutrophil innate immune function, namely, apoptosis, priming, and generation of an intracellular oxidative burst, are altered, most prominently during febrile attacks, in children with PFAPA syndrome.

On the road to discovery in periodic fever, aphthous stomatitis, pharyngitis and adenitis (PFAPA) syndrome.

Profile of blood cells and inflammatory mediators in periodic fever, aphthous stomatitis, pharyngitis and adenitis (PFAPA) syndrome.

This study aimed to profile levels of blood cells and serum cytokines during afebrile and febrile phases of periodic fever, aphthous stomatitis, pharyngitis and adenitis (PFAPA) syndrome to advance pathophysiological understanding of this pediatric disease. A cohort of patients with a median age of 4.9 years experiencing 'typical PFAPA' episodes participated in this study. Blood cells and serum cytokines were analyzed by CBC analysis and multiplex ELISA. Oscillations in the concentration of blood cells during the afebrile and febrile phases of typical PFAPA syndrome were observed; novel findings include increased monocytes and decreased eosinophils during a febrile episode and increased thrombocytes in the afebrile interval. Relatively modest levels of pro-inflammatory cytokines were present in sera. IFNγ-induced cytokine IP10/CXCL10 was increased after the onset of fever while T cell-associated cytokines IL7 and IL17 were suppressed during afebrile and febrile periods. Identification of dysregulated blood cells and serum cytokines is an initial step towards the identification of biomarkers of PFAPA disease and/or players in disease pathogenesis. Future investigations are required to conclusively discern which mediators are associated specifically with PFAPA syndrome.