Scientists identify new treatment to combat PFAPA syndrome in children

Published on April 11, 2011 at 2:11 AM · 10 Comments

A preliminary study conducted by a team at the National Institutes of Health has identified a promising new treatment in children for the most common form of a rare disorder. The syndrome is called periodic fever associated with aphthous stomatitis, pharyngitis and cervical adenitis - or PFAPA - and is characterized by monthly flare-ups of fever, accompanied by sore throat, swollen glands and mouth lesions.

The proposed treatment, which will be validated in a larger study before it is recommended in treating PFAPA syndrome, wards off an inappropriate immune system attack without increasing the frequency of flare-ups, a problem caused by the current standard treatment with corticosteroids. 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.

"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 PFAPA episode. Affected children experience their first attack before the age of 5, with fever episodes usually abating in adolescence or young adulthood. The only remedy for PFAPA, besides corticosteroids, is removal of an affected child's tonsils, which has a good rate of success in eliminating PFAPA syndrome, but is an invasive alternative.

The new experimental treatment resulted from the researchers using a systems biology approach, which entailed gene and protein expression and cell biology analysis in carefully selected patient and healthy control subjects, to determine the underlying disturbance of the immune system. They analyzed patient blood samples to detect which gene and protein networks are involved in the cell signaling and metabolic pathways activated in 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 and intervening periods when the children were well. The analysis revealed gene expression profiles that uniquely identified PFAPA immune response.

"Gene profiles during PFAPA flares are remarkably distinct from when children are asymptomatic," said Dr. Kastner, noting that the analysis also distinguished PFAPA syndrome from other periodic fevers. But 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 response-the 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 related to microbial infection.

The researchers looked for biological markers that would indicate the onset of a flare-up of fever in children with PFAPA. During PFAPA flare-ups, the researchers detected decreased numbers of activated T cells, white blood cells that play a role in the cell's innate immune response. They suspect that these activated T cells migrated to the lymph nodes in the neck, where they accumulate. They also detected over-expression of genes activated in innate immune responses, including interleukin-1, a molecule that is important in triggering fever and inflammation.

From these data, the researchers hypothesized that anakinra, a drug that prevents interleukin-1 from binding to its receptor, could be therapeutic. They administered anakinra by injection to five children on the second day of their PFAPA fevers and all showed a reduction in fever and inflammatory symptoms within hours.

"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."

A larger clinical trial for the use of anakinra in treating this periodic fever syndrome is planned, Dr. Kastner said.

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Comments
  1. Rita Renault Rita Renault Brazil says:

    I hope you get to do the clinical trial. The kids and the their families would be very gratefull .
    Thank you very much for your help,
    Rita and family

  2. Noelle Martin Noelle Martin United States says:

    I am a medical student and I am doing a research project on any disease, and I chose PFAPA. I would love any more info or pictures you could email me. Thank you

  3. Rebeccah M Rebeccah M United States says:

    Really hope better treatment can be found and doctors can be better educated in diagnosing and treating PFAPA.  I have four little boys who have suffered with this since each was just a few months old.  Finally my oldest outgrew it.  I don't think I could handle any more with this.  My little guys fight fevers of 105-108, two have suffered multiple seizures, and all have had to miss out on so much in life . For my children it has sometimes been a fight for their lives, so THANK YOU to you doctors and scientists who study to find answers to our children's suffering.

    • Adriana Cardenas Adriana Cardenas United States says:

      Wow! God bless you with your four little ones.  It is difficult enough to deal with one child going through this.  Have you tried the removal of their tonsils.  I am still not sure what to do with my little one.

    • t isl t isl United States says:

      Rebeccah, your story has me in tears.  My warmest wishes for health to your family.  My son began his fevers at age 2 and is 3 years old now.  His pediatrician has little knowledge of FPAPA therefore I feel I have no where to turn. Five months back a specialist diagnosed him and since then prescribed Orapred to give at onset of fever.  This usually works very well and fever disappears.  This time, my son had 3 episodes of fever in a span of 5 days.  Is there any other options? Its been so difficult to witness a little child go through something like this.

  4. ALICIA PEREZ ALICIA PEREZ United States says:

    My son suffered from this syndrome starting at age 3, with a fever of 105-106 and febrile seizure. He continued having the monthly high fever, exudative pharyngitis, cervical adenitis, sever chills, lasting usually 3-4 days, associated with abdominal discomfort and lack of appetite until age 6.
    Afterwards they occured less frequently then as a teenager he had similar episodes with stress or travel. As older child he had less adenitis and max fever 102-103, and had mouth sores. As an adult he has oral sores with stress, trauma and some foods. Problem was that he was born in 1980 and never had a diagnosis, I was blamed He missed a lot of school, and there was a lot of family disruption and sibling issues on account of his chronic illness. He was treated with phenobarbitol for one year to avoid the recurrence of seizures.
    His daughter started the same pattern, beginning at 12 months and has been referred to NIH at 19 months. I think there is still little awareness of PFAPA and it has been difficult to get her diagnosed despite my profession and experience.

  5. Kim H. Kim H. United States says:

    After missing 54 days of kindergarten and being sick every 3 weeks for months and months, our daughter was diagnosed with PFAPA when she was 6.  Under the guidance of doctors at Children's Memorial in Chicago, we spent a year treating the syndrome with Prednisone. We were unhappy with the unpredicatability of her 'episodes' as well as possiblity of giving her the Prednisone when the fever was not due to the PFAPA (ie:  fever due to an ear infection- pain arrived the day after the fever).  We decided to take out her tonsils and adnoids.  She did not have any other 'episodes' after that--HOORAY!    

    But..... now she is 18, and she is she has been getting sick frequently with high fever and swollen glands/lymphnodes.   Has anyone heard of this coming back after 11 years free of PFAPA illness/episodes?

    • Barbara Castellano Barbara Castellano United States says:

      My daughter had severe sore throats when younger, sometimes strep sometimes not. Began having more frequent episodes of high fevers, terrible sore throats about 1and ahalf yrs ago. She choose to get her tonsils removed August 2013. Has had at least four or five episodes of high fevers and severe sore throats lasting about 4-6 days since. Very frustrating. Her ENT is on board with the dx of PFAPA and I am also goin to take her to see an infectious disease dr.  Frustrating and discouraging. Not much you can do for your child when they are sick like this!

  6. amy warnke amy warnke United States says:

    My daughter started having fevers at age 2 and now 6 years later we are still battling them every 30 days.  They put her on prednisone and it worked for about six months and now it might take it down a little but most times not at all. We have seen 3 doctors and set up to see a fourth.  I sure hope they come up with something soon. As she gets older they are affecting her more and the recovery time is longer.  Very frustrated!!

  7. Jessica Cole Jessica Cole United States says:

    My son was diagnosed with PFAPA in July 2013 at Seattle Children's Rheumatology.  Since, he has taken Cimetidine orally every 12 hours.  He didn't miss any school in 2013-2014 due to PFAPA!  Year prior, 27 days missed.  Cimetidine has worked wonders and changed his life.  After 6 months on Cimetidine 2 times daily, we started tapering down, eliminating a dose per month.  When we were down to 7 doses weekly, we had an 3 episodes in 3 days, even prednisone wasn't helping much.  So we sit at 9 doses a week, and have been healthy for 3 months. Smile  this is so hard to deal with I really do understand.  Sincerely, Jessica

The opinions expressed here are the views of the writer and do not necessarily reflect the views and opinions of News-Medical.Net.
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