role of tonsillectomy in pfa pa syndrome

ORIGINAL ARTICLE

Role of Tonsillectomy in PFAPA SyndromeKevin K. Wong, MD; Jane C. Finlay, MD, FRCPC; J. Paul Moxham, MD, FRCSC

Objective: To examine the efficacy of tonsillectomyin ameliorating symptoms and preventing recurrenceof episodes in children with PFAPA syndrome (peri-odic fever, aphthous stomatitis, pharyngitis, andadenitis).

Design: Retrospective case series.

Setting: Tertiary care children’s hospital.

Patients: Patients who presented to a major tertiaryteaching hospital in Vancouver, British Columbia, Canada,between 2000 and 2004 with the diagnosis of PFAPA syn-drome or for whom the diagnosis was made on their ini-tial consultation.

Intervention: Tonsillectomy.

Main Outcome Measures: Resolution of symptomsat 3, 12, and 24 months after tonsillectomy.

Results: Eight of the 9 patients achieved complete re-mission within 3 months. In the remaining patient, thefrequency of episodes decreased from every 2 weeks toonce every 3 to 4 months. This patient eventually hadresolution of symptoms at 2 years after tonsillectomy. Nocomplications resulted from the tonsillectomy.

Conclusion: Tonsillectomy is a viable treatment optionfor patients with PFAPA syndrome.

Arch Otolaryngol Head Neck Surg. 2008;134(1):16-19

M ARSHALL SYNDROME, OR

PFAPA syndrome (pe-riodic fever, aphthousstomatitis, pharyngi-tis, and adenitis), was

first described in 1987 by Marshall et al.1

This clinical syndrome usually manifests inchildren younger than 5 years. Periodic fe-vers (temperature �39°C) last from 3 to 6days and occur at fixed intervals approxi-mately every 3 to 6 weeks. Along with aph-thous stomatitis, pharyngitis, and cervicaladenitis, other less common symptoms havebeen observed including malaise, head-aches, abdominal pain, vomiting, hepato-splenomegaly, and arthralgias.2,3 Childrenare usually well between episodes. The con-dition lasts a mean of 4.5 years.

While many theories exist, the exactcause of PFAPA syndrome is unknown. In-fectious causes (bacterial and viral) havefor the most part been ruled out as poten-tial causes through cultures and sero-logic and skin tests. Theories involving au-toimmune and rheumatologic disordershave also been disproved. As well, no geo-graphic or ethnic predilection has beenfound among patients. Diagnosis is madeon a clinical basis because no definitivelaboratory tests can positively identifyPFAPA syndrome. During acute epi-

sodes, white blood cell (WBC) count anderythrocyte sedimentation rate (ESR) areconsistently elevated in these patients.1

Treatments for PFAPA syndrome arebased primarily on case series or retro-spective medical chart reviews. To ourknowledge, no controlled studies exist inthis area. Treatment has predominantlyconsisted of oral steroids. In one study,prednisone was prescribed for patientswith PFAPA resulting in a 76% improve-ment in symptoms.4 However, predni-sone did not prevent further episodes andon occasion resulted in shorter intervalsbetween episodes in some patients.4 Ci-metidine has also been used to prevent re-currences and reduce severity of the con-dition, but its success is limited.5 Severalsmall series of case reports have been pub-lished within the past decade describingthe use of tonsillectomy in patients withPFAPA. Tonsillectomy has improvedsymptoms, based on limited data.6 Herein,we describe 9 patients with PFAPA syn-drome who underwent tonsillectomy.

METHODS

We undertook a retrospective case series analy-sis of all patients who presented to the BritishColumbia Children’s Hospital between Janu-

Author Affiliations: Division ofOtolaryngology, Department ofSurgery (Drs Wong andMoxham), and Division ofGeneral Pediatrics andInfectious Diseases, Departmentof Pediatrics (Dr Finlay), BritishColumbia’s Children’s Hospital,Vancouver, British Columbia,Canada.

(REPRINTED) ARCH OTOLARYNGOL HEAD NECK SURG/ VOL 134 (NO. 1), JAN 2008 WWW.ARCHOTO.COM16

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ary 1, 2000, and December 31, 2004, with the diagnosis ofPFAPA syndrome or for whom the diagnosis was made on ini-tial consultation. Patients who met the above criteria then un-derwent tonsillectomy by 1 surgeon (J.P.M.). The procedurewas discussed in detail with the parents, and consent was ob-tained. All patients were observed for a minimum of 24 monthsafter surgery, and recurrence of disease, intervals between epi-sodes (if complete remission of symptoms was not obtained),and any complications arising from the surgical procedure werenoted. Ethics approval was obtained for this study from the clini-cal ethics review board at the University of British Columbia.

RESULTS

A total of 9 patients were identified with PFAPA syn-drome, 5 boys and 4 girls. The mean age at presentationwas 4.1 years (age range, 3-5 years). The fevers exhib-ited by these patients lasted for a mean of 4.1 weeks andoccurred within 2 to 6 weeks of the onset of illness.None of the patients had any prior medical treatment.All 9 patients were observed for a minimum of 24months after tonsillectomy. Complete remission wasachieved in 8 of the 9 patients within 3 months of per-forming the tonsillectomy. In the patient who did notachieve immediate remission, the frequency of attacksdropped from every 2 weeks to every 3 to 4 months. Thepatient’s symptoms eventually resolved by 24 monthspostoperatively (Table 1). No complications (minoror major) occurred in any of the patients as a result oftonsillectomy.

COMMENT

The symptoms that make up PFAPA syndrome, espe-cially fever and pharyngitis, are commonly observed inan otolaryngology setting. Marshall et al1 note that peri-odic fevers were first described as early as the 1940s,but PFAPA syndrome has only been recognized for thepast 2 decades. Consequently, prior to its recognition,cases of PFAPA syndrome may have been incorrectlydiagnosed as other syndromes or diseases that share itssymptoms and signs. When considering the diagnosis

of PFAPA syndrome, the physician must have a clearknowledge and understanding of the differential diag-nosis that includes syndromes such as cyclic neutrope-nia, hereditary fevers, and Behcet disease. These dis-eases must be ruled out before PFAPA syndrome can becorrectly diagnosed: PFAPA syndrome is a diagnosis ofexclusion.

Cyclic neutropenia is rarer than PFAPA syndrome, butthe 2 conditions are almost clinically indistinguishable. Incyclic neutropenia, episodes recur about every 21 days(range, 14-35 days) and are often associated with aph-thous ulcers, gingivitis, cervical lymphadenopathy, and fe-ver. The neutropenia occurs as a result of oscillatory pro-duction of neutrophils by the bone marrow. During theneutropenic period, the polymorphonuclear leukocyte(PMN) count is generally reduced to lower than 200 cells/µLfor 3 to 5 days, with rapid recovery to normal levels. (Toconvert PMNs to number of cells�109 per liter, multiplyby 0.001.) During the symptomatic period, the PMN countmay have already recovered. Therefore, diagnosis re-quires twice-weekly complete blood cell counts, ideally for6 weeks, or at least starting 2 weeks prior to the expectedfebrile episode. Histologically, bone marrow shows matu-rational arrest at the myelocyte stage. Treatment usuallyinvolves granulocyte colony–stimulating factor.7

Hereditary periodic fevers are a generalized group ofdiseases that include familial Mediterranean fever (FMF),hyper-IgD syndrome, and Hibernian fever. Familial Medi-terranean fever is an autoinflammatory disease charac-terized by periodic attacks of fever and serositis. It is anautosomal recessive disease occurring mainly in pa-tients of Turkish, Armenian, Arab, and Sephardic Jew-ish descent. The recurrent attacks of fever are accompa-nied by severe abdominal pain, arthritis, and/or pleuriticchest pain along with a marked increase in level of acute-phase reactants.8 The diagnosis of FMF should be con-sidered in individuals of an appropriate ethnic back-ground who present with febrile disease of an episodicnature. Colchicine is recognized as the primary treat-ment because it controls the attacks and prevents the de-velopment of amyloidosis.9

Table 1. Study Patient Clinical Characteristics and Episode Outcomes After Tonsillectomy

PatientNo.

Age at Onset(Initial Consult),

y Symptoms

SymptomPeriod,

wk

Postsurgical Outcome

3 mo 1 y 2 y

1 4 (6) F, A, P 4 Resolved Resolved Resolved2 5 (7) F, A, P 2 Frequency decreaseda Frequency decreaseda Resolved3 3 (5) F, A, Aph, P 6 Resolved Resolved Resolved4 4 (5) F, A, Aph, P 4 Resolved Resolved Resolved5 5 (5) F, A, P 4 Resolved Resolved Resolved6 4 (6) F, A, Aph, P 5 Resolved Resolved Resolved7 4 (5) F, A, Aph, P 4 Resolved Resolved Resolved8 5 (5) F, A, P 4 Resolved Resolved Resolved9 5 (6) F, Aph, P 4 Resolved Resolved Resolved

Abbreviations: A, cervical adenopathy; Aph, aphthous ulcers; F, periodic fevers; P, pharyngitis; PFAPA, periodic fever, aphthous stomatitis, pharyngitis, andadenitis.

aThis patient continued to have PFAPA episodes, but frequency was less than once every 3 to 4 months; by 1 year after surgery, the patient had experienced3 episodes.



Similar to PFAPA syndrome, hyper-IgD syndrome usu-ally first presents at a very early age (median age at on-set, 6 months) and involves a periodic fever. Fevers char-acteristically last for 3 to 7 days, and the attacks typicallyoccur every 4 to 8 weeks. As the patient ages, the fre-quency and severity of attacks decreases. However, fe-ver episodes differ from those of PFAPA syndrome epi-sodes in that they usually continue to occur throughoutthe patient’s life. Other symptoms include chills, lymph-adenopathy, abdominal pain, vomiting, diarrhea, andheadaches. During attacks, an acute-phase response isdemonstrated by leukocytosis, neutrophilia, and an in-creased erythrocyte sedimentation rate. Elevated serumIgD and IgA levels (�100 U/mL) are characteristic butnot always present; repeated testing may be required dur-ing these episodes. The cause of this disease is believedto be a mutation of the MVK gene that encodes for meva-lonate kinase. Treatment consists mainly of supportivetherapy.10,11 Recent studies examining treatment with thedrug etanercept, a tumor necrosis factor receptor Fc fu-sion protein, have yielded mixed results regarding itseffectiveness.12,13

Behcet disease is a multiple-organ disease character-ized by oral aphthae and by at least 2 of the following:(1) genital aphthae, (2) synovitis, (3) posterior uveitis,(4) cutaneous pustular vasculitis, (5) meningoencepha-litis, (6) recurrent genital ulcers, and (7) uveitis in theabsence of inflammatory bowel disease or collagen vas-cular disease.14 Similar to PFAPA, no pathognomonic labo-ratory test exists, but clinical criteria can assist in estab-lishing the diagnosis.15 Behcet disease does not usuallyinvolve febrile episodes, and oral ulcers are more severethan in PFAPA syndrome. These characteristic symp-toms of Behcet disease help to distinguish it from PFAPAsyndrome.

A review of the literature examining the utility of ton-sillectomy in the treatment of patients with PFAPA syn-drome2,5,6,16-18 reveals 6 articles describing a total of 41documented cases (Table 2). A substantial decrease inthe frequency of PFAPA episodes occurred in greater than84% of patients (37 of 44). Most authors who have stud-ied tonsillectomy in PFAPA syndrome conclude that ton-sillectomy can be considered a viable treatment option.The inherent problem with the current literature is thatit is based solely on retrospective case series (level 5 evi-dence). Leong et al19 argue that some patients diag-nosed as having PFAPA syndrome may have merely ex-

perienced a recurrent infection and that completeresolution of symptoms would be expected after the pro-cedure. In our case series, 89% of patients experiencedresolution of their symptoms (8 of 9), which is similarto the data found in the literature. For the 1 patient inour series who did not experience complete resolutionof symptoms, the frequency of episodes decreased. By 2years after the tonsillectomy, he had experienced com-plete resolution of symptoms. Whether this was a directresult of the tonsillectomy or due to the self-resolvingnature of the disease is not known.

Although PFAPA syndrome has an eventual self-limiting course, most authors recommend that treat-ment be initiated relatively promptly once the diagnosisis made. Medical management (ie, steroids and cimeti-dine) is the most common treatment used. Tonsillec-tomy is not yet considered a mainstay of treatment, butboth medical and surgical management have demon-strated success in the resolution of symptoms. Currentmedical management supports the use of steroid treat-ment. Various dosages of oral prednisone have been pro-posed, with the dose of 1 to 2 mg/kg given as a singledose being the most commonly used. Other approachesinclude an escalating 7-day dose regimen or alternate-potency steroid preparations (eg, every-other-day ad-ministration of prednisone at 2 mg/kg/d and betametha-sone at 0.3 mg/kg/d given on alternating days). Twice dailydoses of cimetidine at 150 mg by mouth for 6 monthshas also been used with some success. Cimetidine is anH2 antagonist that inhibits chemotaxis and T-cell acti-vation. Thomas and Edwards4 found that 8 of 28 pa-tients treated with cimetidine had complete remission oftheir symptoms.

The use of nonsteroidal anti-inflammatory agents hasshown poor results in controlling symptoms of PFAPAsyndrome. Acetaminophen and ibuprofen reduced fe-ver in 6% and 33% of patients, respectively, but once thedrugs’ effects had worn off, the fevers returned.2 Othermedications, including antibiotics, acyclovir, and col-chicines, have provided minimal if any relief of symp-toms.4 Complications related to a single dose of steroidsare extremely rare in children20; however, the potentialrisks should be explained to parents.

Tonsillectomy is the only surgical option found to im-prove symptoms in patients with PFAPA syndrome. Toour knowledge, no studies have examined the use of neo-adjuvant or adjuvant medical treatment with tonsillec-

Table 2. Reported Outcomes for PFAPA Syndrome Treated With Tonsillectomy

Source YearPatients,

No.CompleteResolution

Prior Treatment(Patients, No.)

Tasher et al18 2006 6 6 NoneParikh et al16 2003 2 0 Cimetidine (1)Berlucchi et al5 2003 5 5 Steroids (5)Galanakis et al6 2002 15 15 NoneDahn et al17 2000 4 4 NoneThomas et al2 1999 11 7a Steroids (NR)

Abbreviations: NR, not reported; PFAPA, periodic fever, aphthous stomatitis, pharyngitis, and adenitis.a In addition, 2 patients experienced partial resolution, retaining some residual postsurgical symptoms.



tomy in patients with PFAPA syndrome. The exact rolethat tonsillectomy plays in symptom resolution is un-clear, but the syndrome may be caused by an immuneresponse generated in the tonsillar parenchyma.5 Thereappears to be no difference in patient outcome whetheror not an adenoidectomy was performed alongside of thetonsillectomy. However, adenoidectomy by itself did notresult in resolution of symptoms.2 No complications wereexperienced by any patients in our study. We found inthe literature no documented complications of tonsil-lectomy performed in patients with PFAPA syndrome.There is no reason to expect potential higher tonsillec-tomy complication rates in patients with PFAPA than inother patients.

In conclusion, PFAPA syndrome is an uncommon con-dition, and its diagnosis is one of exclusion. With the ex-ception of tonsillectomy, treatment is primarily medicalconsisting of steroid therapy. Treatment options such asprednisone, cimetidine, or tonsillectomy have demon-strated success in decreasing or completely resolvingsymptoms. Treatment is based on the theory that PFAPAsyndrome is caused by dysregulation of the immune re-sponse. According to this theory, if the aberrant im-mune response is curtailed, the symptoms will resolve.We have observed excellent results with tonsillectomyin 8 of 9 patients in our study who exhibited completeremission of their symptoms after tonsillectomy. The re-maining patient initially experienced a dramatic de-crease in the frequency of attacks and had resolution ofsymptoms by 24 months.

Because PFAPA syndrome is a relatively newly rec-ognized clinical entity, more research needs to be con-ducted to determine the optimum treatment. From ourexperience, we found that in a child who is a good sur-gical candidate, tonsillectomy is a viable treatment op-tion for PFAPA syndrome.

Submitted for Publication: February 9, 2007; final re-vision received August 13, 2007; accepted August 28,2007.Correspondence: J. Paul Moxham, MD, FRCSC, BritishColumbia’s Children’s Hospital, 4500 Oak St, Vancou-ver, BC V6H 3V4, Canada.Author Contributions: Dr Moxham had full access to allthe data in the study and takes responsibility for the in-tegrity of the data and the accuracy of the data analysis.Study concept and design: Moxham. Acquisition of data:Finlay and Moxham. Analysis and interpretation of data:Wong and Moxham. Drafting of the manuscript: Wong andMoxham. Critical revision of the manuscript for impor-tant intellectual content: Finlay and Moxham. Statistical

analysis: Wong. Administrative, technical, and material sup-port: Finlay and Moxham. Study supervision: Moxham.Financial Disclosure: None reported.Previous Presentation: This article was presented at TheAmerican Society of Pediatric Otolaryngology 2007 An-nual Meeting; April 28, 2007; San Diego, California.

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3. Padeh S, Brezniak N, Zemer D, et al. Periodic fever, aphthous stomatitis, phar-yngitis, and adenopathy syndrome: clinical characteristics and outcome. J Pediatr.1999;135(1):98-101.

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12. Takada K, Aksentijevich I, Mahadevan V, Dean JA, Kelley RI, Kastner DL. Favor-able preliminary experience with etanercept in two patients with the hyperim-munoglobulinemia D and periodic fever syndrome. Arthritis Rheum. 2003;48(9):2645-2651.

13. Marchetti F, Barbi E, Tommasini A, Oretti C, Ventura A. Inefficacy of etanerceptin a child with hyper-IgD syndrome and periodic fever. Clin Exp Rheumatol. 2004;22(6):791-792.

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15. Lee LA. Behcet disease. Semin Cutan Med Surg. 2001;20(1):53-57.16. Parikh SR, Reiter ER, Kenna MA, Roberson D. Utility of tonsillectomy in 2 pa-

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20. Steward DL, Welge JA, Myer CM. Steroids for improving recovery following ton-sillectomy in children. Cochrane Database Syst Rev. 2003;(1):CD003997.



role of tonsillectomy in pfa pa syndrome

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