|The new proposed treatment - still to be tested in a larger study before suggesting it as treatment for PFAPA - targets an inappropriate immune system attack.
"Until now, the basis of PFAPA has been a mystery," said senior author and NHGRI Scientific Director Daniel Kastner, M.D., Ph.D. "Advances in genomic analysis have allowed us to define a major role for the innate immune system, the body's first line of defense against infection. Targeting a specific product of white blood cells at the first sign of fever appears to abort the attacks."
Children with PFAPA syndrome experience attacks of fever, each lasting three to six days, usually three to eight weeks apart. Their predictability is so regular that parents have been known to make pediatric appointments a week ahead of when they expect their child to experience a fever episode. Affected children experience their first attack before the age of 5, with fevers usually slowing down and stopping in adolescence or young adulthood.
The only remedy for PFAPA is currently corticosteroids, or removal of an affected child's tonsils, which has a good rate of success in eliminating PFAPA syndrome, but is invasive surgery.
So, researchers looked for biological markers that would indicate the onset of a flare-up of fever in children with repeating illness.
During PFAPA flare-ups, the scientists detected decreased numbers of activated T cells, white blood cells that play a role in the cell's innate immune response. They also detected over-expression of genes usually activated in innate immune responses, including interleukin-1, a molecule that is important in triggering fever and inflammation.
From this information, they hypothesized that anakinra, a drug that prevents interleukin-1 from binding to its receptor, migh be therapuetic. After administering anakinra by injection to five children on the second day of their PFAPA fevers, all five showed a reduction in fever and inflammatory symptoms within hours.
The new treatment resulted from using a systems biology approach, which compares gene and protein expression between healthy and sick populations, to determine the underlying immune response. By analyzing patient blood samples, they detected which gene and protein networks were involved in the cell signaling and metabolic pathways of the disease.
The research group studied 21 patients with PFAPA syndrome along with an equal number of healthy children and 12 children with a distinctly different set of hereditary fever syndromes. They analyzed gene expression during episodes of fever compared to when the children were well. The analysis revealed gene expression profiles that uniquely identified PFAPA immune response.
When PFAPA patients are asymptomatic, their gene expression is similar to healthy children.
During PFAPA flare ups, the researchers detected activation of both forms of immune responsethe innate, first-line-of-defense immunity, and adaptive immunity, which is the body's ability to detect and remember an infection in order to fight it later. This dual response supports the idea that the fevers of PFAPA are an immunologic response to some external stimulus, possibly microbial infection.
"The anakinra treatment has the potential to restore these children to a mostly symptom-free childhood," said Dr. Kastner. "The comprehensive analysis of gene expression during PFAPA attacks would not have been possible without the tools created by the Human Genome Project, and the possibility of an effective treatment is yet another of the genome project's many dividends."
The team of researchers from the National Human Genome Research Institute (NHGRI) and the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) reported their findings in the April 8, 2011, early online edition of the Proceedings of the National Academy of Sciences.
NHGRI is one of the 27 institutes and centers at the NIH, an agency of the Department of Health and Human Services. The NHGRI Division of Intramural Research develops and implements technology to understand, diagnose and treat genomic and genetic diseases. Additional information about NHGRI can be found at its website, www.genome.gov.