Q:

5/9/2012
I saw an 18 year old female yesterday who presented with a history of periodic fever (102 F now, as a child to 104), cervical adenitis, pharyngitis, past history of associated aphthous stomatitis, since age 2 years. The episodes occur every 5-6 weeks, last 2-3 days, and resolve spontaneously. The problem cleared in her early teenage years, only to recur since age 15. She has a male cousin who now is developing symptoms. Apparently this syndrome was first reported over a decade ago. To my knowledge no abnormal lab or immunology studies have been identified in the literature. Her basic laboratory and immunology studies performed years ago were WNL. The literature suggests a single dose of prednisone taken on day of onset of symptoms for therapy. She has not used prednisone. Is there information regarding interferon on cytokine abnormalities, or alternatives to prednisone treatment in such patients? She has not tried prednisone. A CBC and differential has been ordered at the tim of her next episode to R/O cyclic neutropenia.

A:

Thank you for your inquiry.

There have been some fairly recently published articles dealing to some extent with potential mediators involved in the production of the PFAPA syndrome. I have copied abstracts for you below from this body of literature as well as a link to a commentary regarding one of these studies. The link is to the title "On the road to discovery in periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA) syndrome" (Brown, et al.).

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3161541/?tool=pubmed

Unfortunately, from a practical standpoint however, I am afraid that none of this, at least to my knowledge, to date has led to any change in therapy, which still remains prednisone. One of the abstracts copied below also mentions treatment in this regard.

Finally, we have approached this problem a little differently with a response to a previous inquiry submitted to our website about this syndrome when its major manifestation is recurrent aphthous stomatitis. That previous response was entitled

"Recurrent gingivostomatitis" and was posted on 3/30/2012.

Since, from reading your question, your patient no longer has aphthous stomatitis with these episodes, this response may not be of interest to you. However, it does discuss the potential use of the Tzanck smear or biopsy to make an etiologic diagnosis when stomatitis is present.

Thank you again for your inquiry and we hope this response is helpful to you.

Proc Natl Acad Sci U S A. 2011 Apr 26;108(17):7148-53. Epub 2011 Apr 8.
Periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA) is a disorder of innate immunity and Th1 activation responsive to IL-1 blockade.
Stojanov S, Lapidus S, Chitkara P, Feder H, Salazar JC, Fleisher TA, Brown MR, Edwards KM, Ward MM, Colbert RA, Sun HW, Wood GM, Barham BK, Jones A, Aksentijevich I, Goldbach-Mansky R, Athreya B, Barron KS, Kastner DL.
Source
National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Abstract
The syndrome of periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) is the most common periodic fever disease in children. However, the pathogenesis is unknown. Using a systems biology approach we analyzed blood samples from PFAPA patients whose genetic testing excluded hereditary periodic fevers (HPFs), and from healthy children and pediatric HPF patients. Gene expression profiling could clearly distinguish PFAPA flares from asymptomatic intervals, HPF flares, and healthy controls. During PFAPA attacks, complement (C1QB, C2, SERPING1), IL-1-related (IL-1B, IL-1RN, CASP1, IL18RAP), and IFN-induced (AIM2, IP-10/CXCL10) genes were significantly overexpressed, but T cell-associated transcripts (CD3, CD8B) were down-regulated. On the protein level, PFAPA flares were accompanied by significantly increased serum levels of chemokines for activated T lymphocytes (IP-10/CXCL10, MIG/CXCL9), G-CSF, and proinflammatory cytokines (IL-18, IL-6). PFAPA flares also manifested a relative lymphopenia. Activated CD4(+)/CD25(+) T-lymphocyte counts correlated negatively with serum concentrations of IP-10/CXCL10, whereas CD4(+)/HLA-DR(+) T lymphocyte counts correlated positively with serum concentrations of the counterregulatory IL-1 receptor antagonist. Based on the evidence for IL-1β activation in PFAPA flares, we treated five PFAPA patients with a recombinant IL-1 receptor antagonist. All patients showed a prompt clinical and IP-10/CXCL10 response. Our data suggest an environmentally triggered activation of complement and IL-1β/-18 during PFAPA flares, with induction of Th1-chemokines and subsequent retention of activated T cells in peripheral tissues. IL-1 inhibition may thus be beneficial for treatment of PFAPA attacks, with IP-10/CXCL10 serving as a potential biomarker.

Eur Cytokine Netw. 2006 Jun;17(2):90-7.
Cytokine profile in PFAPA syndrome suggests continuous inflammation and reduced anti-inflammatory response.
Stojanov S, Hoffmann F, Kéry A, Renner ED, Hartl D, Lohse P, Huss K, Fraunberger P, Malley JD, Zellerer S, Albert MH, Belohradsky BH.
Source
Department of Infectious Diseases and Immunology, Children's Hospital, University of Munich, Germany.
Abstract
PFAPA syndrome is characterized by periodic episodes of high fever, aphthous stomatitis, pharyngitis, and/or cervical adenitis. It is of unknown etiology and manifests usually before 5 years of age. We determined serum and intracellular cytokine levels in six PFAPA patients (4 males, 2 females, mean age 8 years (+/- 1.2 SEM), range 4-13) during the symptom-free period as well as 6-12 hours and 18-24 hours after fever onset. Values were compared to age-matched, healthy controls. Febrile PFAPA attacks led to a significant increase in IL-6 and IFN-gamma serum concentrations compared to symptom-free periods and to controls, with IL-1beta, TNF-alpha and IL-12p70 levels being significantly higher than in controls. Lymphocytic IFN-gamma and CD8+ IL-2 production was consistently significantly elevated compared to healthy children. During the asymptomatic period, serum concentrations of IL-1beta, IL-6, TNF-alpha and IL-12p70 were significantly increased compared to controls. Intracellular TNF-alpha synthesis was not elevated at any time point. Soluble TNFRp55 levels were even lower in between febrile episodes, reaching values comparable to controls during attacks, whereas soluble TNFRp75 levels increased during attacks compared to healthy children. Anti-inflammatory IL-4 in serum was at all times lower in PFAPA patients compared to controls with no difference in levels of intracellular IL-4 and IL-10 or serum IL-10. The observed increase of pro-inflammatory mediators, even between febrile attacks, suggests a dysregulation of the immune response in PFAPA syndrome, with continuous pro-inflammatory cytokine activation and a reduced anti-inflammatory.

Isr Med Assoc J. 2008 May;10(5):358-60.
Periodic fever accompanied by aphthous stomatitis, pharyngitis and cervical adenitis syndrome (PFAPA syndrome) in adults.
Padeh S, Stoffman N, Berkun Y.
Source
Department of Pediatrics A, Safra Children's Hospital, Sheba Medical Center, Tel Hashomer, Israel.
Abstract
Background: The new syndrome, known as PFAPA, of periodic fever characterized by abrupt onset of fever, malaise, aphthous stomatitis, tonsillitis, pharyngitis and cervical adenopathy has been described only in pediatric patients. It usually begins before the age of 5 years and in most cases resolves spontaneously before age 10.
Objectives: To describe a series of adults with PFAPA syndrome.
Methods: This 6 year retrospective descriptive study includes all newly diagnosed incident adult cases aged 18 years and over referred to our center with symptomatology suggestive of PFAPA syndrome. Patients' medical records were reviewed for past history of the disease, demographic characteristics, symptoms and signs, course of the disease, laboratory findings, and outcome following corticosteroid therapy. The comparison group included our pediatric cohort children (N=320, age 0-18 years) followed for the last 14 years (1994-2008).
Results: Fifteen adult patients were diagnosed with PFAPA syndrome. Episodes of fever occurred at 4.6 +/- 1.3 week intervals, beginning at the age of 20.9 +/- 7.5. All patients had monthly attacks at the peak of the disease, with attacks recurring at 4-8 week intervals over the years. Between episodes the patients were apparently healthy, without any accompanying diseases. Attacks were aborted by a single 60 mg dose of oral prednisone in all patients.
Conclusions: This study reports the presence of PFAPA syndrome in adult patients. Although the disease is rare, an increased awareness by both patients and family physicians of this clinical syndrome has resulted in more frequent diagnosis in adult patients.

Neuro Endocrinol Lett. 2010;31(6):743-6.
Elevated immunoglobulin D levels in children with PFAPA syndrome.
Kovacs L, Hlavatá A, Baldovič M, Paulovicova E, Dallos T, Fehérvízyová Z, Kadasi L.
Source
2nd Department of Pediatrics, Comenius University Medical School, Slovakia.
Abstract
Background: The periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis (PFAPA) syndrome appears to be more common than generally appreciated and should be differentiated from hereditary periodic fever syndromes, particularly from mevalonate kinase deficiency (MKD). Patients and methods: 14 unrelated patients (7 males, 7 females) met clinical criteria for both the PFAPA syndrome and MKD. Immunoglobulin D (IgD) levels, mevalonic aciduria and mevalonate kinase (MVK) genotype was determined in all patients.
Results: Children experienced their first febrile episode at the age of 24.5?5.9 months (mean?SD), the clinical diagnosis of PFAPA syndrome was established with delay at 42.7?11.7 months. The duration of febrile episodes was 3.4?0.2 days, the asymptomatic interval between them lasted 5.4?0.9 weeks. Accompanying symptoms included pharyngitis (92.8%), cervical lymphadenitis (85.7%), aphthous stomatitis (21.4%), arthralgia (14.3%) and skin erythema (35.7%). Neither mevalonic aciduria nor MVK gene mutations were found in any of the subjects, however, unexpectedly, increased plasma IgD (322.2?29.2 U/l) levels were detected in all patients.
Conclusion: Raised IgD levels may represent a non-specific epiphenomenon, which frequently accompanies PFAPA syndrome as well as MKD. Because of the overlapping clinical and laboratory features, genetic testing of the MVK gene is indicated to differentiate these two conditions, if clinical criteria for both are fulfilled.

Sincerely,
Phil Lieberman, M.D.

AAAAI - American Academy of Allergy Asthma & Immunology