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Utility of Tonsillectomy in 2 Patients With the Syndrome of Periodic Fever, Aphthous Stomatitis, Pharyngitis, and Cervical Adenitis

Utility of Tonsillectomy in 2 Patients With the Syndrome of Periodic Fever, Aphthous Stomatitis,... ObjectivesTo review the various causes of period fever in childhood, including the syndrome of periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA), and to examine the value of tonsillectomy in the treatment of PFAPA syndrome.DesignRetrospective case series.SettingUrban and tertiary care referral children's hospital.PatientsTwo patients who underwent tonsillectomy for presumed recurrent adenotonsillitis were later diagnosed as having PFAPA syndrome.InterventionTonsillectomy.Main Outcome MeasureFrequency of PFAPA symptoms before and after tonsillectomy.ResultsNo difference was found in the frequency of PFAPA symptoms after tonsillectomy.ConclusionAlthough a larger series of patients is required, our initial experience suggests that tonsillectomy is not always beneficial for patients with PFAPA syndrome.RECURRENT PHARYNGITIS, frequently accompanied by fever and cervical adenopathy, is a common complaint encountered in any pediatric or pediatric otolaryngology practice. Common causative factors include viral pathogens and bacteria, often Streptococcusspecies. In the latter case, acute episodes typically respond to antibiotic therapy, while tonsillectomy is indicated for patients with frequently recurrent episodes.Also, a variety of noninfectious causes of recurrent pharyngitis and fever have been described, including the "periodic syndromes" cyclic neutropenia, familial Mediterranean fever (FMF), familial Hibernian fever, and hyperimmunoglobulinemia D syndrome.Another periodic syndrome, seldom reported in the otolaryngology literature, is that of periodic fever, cervical adenitis, pharyngitis, and aphthous stomatitis (PFAPA), which was first described by Marshall et alin 1987. Marshall and colleagues identified 12 children who had episodes characterized by the abrupt onset of fever (temperatures as high as 40°C) (100%), malaise (100%), chills (83%), aphthous stomatitis (75%), pharyngitis (75%), and tender cervical lymphadenopathy (67%). Episodes lasted an average of 5 days and occurred at regular 4- to 6-week intervals over the course of several years, usually beginning before the age of 5 years, with the duration of recurrent symptoms from onset to latest follow-up ranging from 1 to 15 years at the time of the report (average duration, 3.9 years). During episodes, the patients did not display any particular susceptibility to infection, and during asymptomatic periods, they were otherwise healthy, normally growing children. The only consistent laboratory abnormalities detected were elevated white blood cell counts (WBCs) and mildly elevated erythrocyte sedimentation rates (ESRs), both of which normalized during asymptomatic intervals. Infectious causes were ruled out by various means, including bacterial and viral cultures, purified protein derivative skin tests, and serologic tests. The results of testing for rheumatologic and autoimmune disorders, including quantitative immunoglobulin levels, antinuclear antibody, anti-DNA antibody, rheumatoid factor, total hemolytic complement, and immune complex levels, were normal or negative.In a subsequent report, Marshall and Edwardsproposed specific diagnostic criteria for this disorder, which they characterized as PFAPA syndrome, after its defining characteristics of periodic fever, aphthous stomatitis, pharyngitis, and adenitis. Their criteria are (1) onset in childhood, usually before the age of 5 years; (2) regularly recurring episodes of fever lasting approximately 5 days, associated with constitutional symptoms and both (a) aphthous stomatitis and/or pharyngitis (with or without cervical adenitis) in the absence of other signs of upper respiratory tract infection and (b) acute inflammatory markers, such as an elevated WBC or ESR; (3) asymptomatic periods, generally lasting less than 10 weeks, or a benign long-term course with no sequelae; (4) exclusion of cyclic neutropenia by serial WBCs before, during, and after symptomatic periods; (5) exclusion of other known periodic syndromes by history, clinical course, and appropriate laboratory studies; and (6) absence of any concurrent immunodeficiency, autoimmune disease, or chronic infection.We describe 2 patients with recurrent pharyngitis, fever, and cervical adenitis refractory to antibiotic therapy and tonsillectomy who were ultimately diagnosed as having PFAPA. We review the diagnostic criteria and treatment for PFAPA, as well as for the other periodic syndromes. Since there is a high likelihood that patients with recurrent pharyngitis will seek otolaryngologic consultation, otolaryngologists should be familiar with the various noninfectious causes of recurrent pharyngitis.REPORT OF CASESCASE 1A 14-year-old white girl presented to our service with a 10-month history of recurrent episodes of cervical lymphadenopathy, fever, and sore throats. She was initially diagnosed as having Epstein-Barr virus (EBV) infection because her serologic tests showed a positive EBV nuclear antigen titer and an elevated level of IgM antibody to EBV viral capsid antigen. Within 1 month of presentation, she underwent excisional biopsy of some persistently prominent right-sided midjugular chain lymph nodes. Pathologic analysis showed chronic inflammatory changes, consistent with nonspecific reactive lymphoid hyperplasia. Over the next few months after biopsy, her lymphadenopathy, which had been predominantly right-sided, became predominantly left-sided. She also continued to have monthly sore throats and fevers lasting 2 to 3 days, which were treated with oral antibiotics.Six months after the patient's initial presentation, a tonsillectomy was performed for presumed recurrent pharyngotonsillitis. For 7 months after tonsillectomy, she continued to have monthly episodes of high fever, cervical lymphadenopathy, and sore throat. She was then symptom free for 2 months, but returned to the office with a persistently enlarged left midjugular lymph node. Fifteen months after her initial presentation, a second excisional biopsy was performed, which again showed reactive lymphoid hyperplasia. After this second biopsy, the patient continued to have recurrent bouts of fever, cervical adenitis, and sore throats. She was seen in consultation by the infectious disease service. Given her protracted course and the negative findings of infectious workup, a diagnosis of PFAPA syndrome was made. She was treated with oral cimeditidine and had no further episodes for 3 months. Unfortunately, she developed urinary retention, which resolved when she stopped taking cimeditidine. Her febrile episodes recurred several months after she discontinued the cimeditidine therapy. At last follow-up, at the age of 16 years, she continued to experience diffuse aphthous stomatitis with accompanying febrile episodes. She otherwise demonstrated no long-term sequelae of her illness.CASE 2A 6-year-old white boy presented to the otolaryngology service with a history of more than 1 year of monthly recurrent fevers (temperatures as high as 38.9°C-40.0°C), which were of sudden onset and lasted 5 to 10 days. With each episode, he demonstrated a diffuse nonexudative pharyngitis, cervical lymphadenopathy (greater on the right side than on the left side), and a variable degree of torticollis or abdominal pain. He was otherwise healthy.Laboratory studies prior to his presentation to our service included multiple WBCs, which were elevated as high as 17.0 × 103/µL during febrile episodes, but normal otherwise. The ESRs were also elevated during episodes, but normalized in asymptomatic periods. Other laboratory studies included multiple throat cultures, serologic testing for EBV and toxoplasmosis, purified protein derivative testing on 2 different occasions, quantitative immunoglobulins, and radiography of the chest, the findings of which were all negative or normal.Each febrile episode was treated with oral antibiotics, but it was unclear if the treatment had any effect on the course of the episodes. Nine months after the patient's symptoms first began, an adenotonsillectomy was performed for presumed recurrent adenotonsillitis. He was well for 3 months after surgery, when he again presented with a severe episode, including sore throat, marked torticollis, and cervical lymphadenopathy. His WBC was 17.0 × 103/µL, and his ESR was 127 mm/h. A computed tomographic scan demonstrated an area of low attenuation in the right retropharyngeal region. The patient was taken to the operating room, where needle aspiration returned a small amount of clear fluid. Gram stain showed gram-positive cocci, but cultures were ultimately negative for organisms. A diagnosis of retropharyngeal phlegmon was made. The patient was treated with 5 days of intravenous cefuroxime therapy, improved, and was discharged home on a regimen of oral cefuroxime. At this point, he was referred to our service for consultation.A magnetic resonance imaging scan of the neck and cervical spine was obtained to rule out an occult source of infection, such as osteomyelitis or a branchial cleft anomaly. An infectious disease consultation was also obtained, and the diagnosis of PFAPA syndrome was made. Because the patient's symptoms were not severe, he has received no further treatment; he continues to have similar recurrent episodes but is otherwise in good health.COMMENTIt is necessary to conclusively rule out other known periodic diseases before making a diagnosis of exclusion, such as PFAPA syndrome. Other diagnoses to consider include cyclic neutropenia, FMF, familial Hibernian fever, hypergammaglobulinemia D, and periodic fever syndrome.Cyclic neutropenia is characterized by recurrent periods of neutropenia due to an abnormality in hematopoiesis.Patients typically present with recurrent fever, malaise, aphthous stomatitis, and cervical adenopathy before the age of 5 years. Cycles occur every 20 to 22 days, with little variation in frequency for any given patient, or between patients, in contrast to the longer cycles experienced by our patients. During symptomatic periods, peripheral neutrophil counts decrease to as low as 0 and remain under 200/µL for 3- to 5-day periods. Furthermore, patients with cyclic neutropenia are susceptible to recurrent infections, such as furunculosis, pneumonia, abscesses, cellulitis, conjunctivitis, and sinusitis, unlike patients with PFAPA syndrome.Several other periodic syndromes have been described that, unlike cyclic neutropenia, are familial. Familial Mediterranean fever, also called recurrent hereditary polyserositis, is an autosomal recessive disorder that is seen primarily in Arabs, Sephardic Jews, and Armenians, and more rarely among Turks, Greeks, and Italians.Manifestations include recurrent episodes of fever, usually beginning before the age of 5 years, of variable frequency (1-40 per year), lasting 2 to 3 days, and associated with one or more of the following: (1) peritonitis, manifested by abdominal pain (90%-95%), (2) arthritis (80%-85%), and (3) pleuritis, manifested by chest pain (20%-40%).Adenopathy, pharyngitis, or aphthous stomatitis is not observed in patients with FMF. Although most patients with FMF do not develop any long-term sequelae, there is a well-documented association with renal amyloidosis and subsequent renal failure in 20% to 60% of affected patients.Although no specific laboratory abnormalities have been identified, patients exhibit significant increases in acute-phase reactants, such as ESR and C-reactive protein, serum haptoglobin, ceruloplasmin, and serum amyloid levels. Rarely, patients will also have an increase in the WBC. These patients experience a marked decrease in the frequency and severity of attacks with oral colchicine therapy. The prominent cervical adenopathy, pharyngitis, and absence of any serosal involvement or family history in our patients strongly argue against FMF as the cause of their recurrent symptoms.A disorder similar to FMF, characterized by recurrent attacks of fever, abdominal pain, tender skin lesions, and myalagias, but demonstrating autosomal dominant inheritance, was identified in an Irish family by Williamson et al.Patients who have this entity, which is called familial Hibernian fever, also demonstrate an increase in WBC and ESR during attacks, have asymptomatic intervals of variable duration, and respond dramatically to the administration of corticosteroids. A similar report from Gertz et aldescribed an American family of German descent with 3 generations afflicted by a disorder quite like FMF, with prominent systemic amyloidosis. In this kindred, inheritance also appeared to be autosomal dominant, and there was no response to colchicine adminstration.In 1984, van der Meer et aldescribed a disorder characterized by recurrent bouts of high, spiking fever accompanied by headache, cervical adenopathy, and occasionally abdominal pain and diarrhea. Most patients developed symptoms before the age of 1 year. Attacks lasted 3 to 7 days and occurred at frequencies varying from weekly to twice per year. Laboratory studies revealed an increase in WBCs and ESRs during symptomatic periods that returned to normal levels between episodes and, most notably, a marked increase in serum IgD levels both during and between episodes.This disorder has been termed hypergammaglobulinemia D and periodic fever syndrome. Its hallmark is the increase in serum IgD levels, a finding that is not present in patients with PFAPA syndrome.Both of our patients clearly meet the diagnostic criteria for PFAPA syndrome. Both had well-defined, regularly recurring episodes of fever, with pharyngitis, significant cervical adenopathy, and transient increases in WBCs and ESRs. It is interesting to note that patient 1 began to exhibit aphthous stomatitis well after the onset of her febrile episodes. Aphthous stomatitis was seen in 75% of the patients in the study of Marshall et al,so its initial absence, as in our patient 2, does not preclude the diagnosis of PFAPA syndrome.Treatment of PFAPA syndrome is controversial. Given the overall benign course of the disorder, no specific treatment might be considered an option. Symptomatic treatment is certainly reasonable in patients with PFAPA syndrome. Aphthous stomatitis can be the most troublesome aspect of PFAPA episodes.A double-blind study reported in the oral surgery literature showed that topical therapy with betamethasone-17-benzoate provided both symptomatic relief and a decrease in the healing time of recurrent aphthous ulcers.In Marshall and colleagues' initial study, treatment with antibiotics or nonsteroidal anti-inflammatory drugs had little effect on symptoms or on the duration or frequency of febrile episodes.Although antibiotic therapy did not have a significant effect on the course of the illness, the occurrence of a retropharyngeal phlegmon in our patient 2 suggests a possible role for prophylactic antibiotic therapy to prevent bacterial superinfection of enlarged cervical lymph nodes.The use of corticosteroids for the treatment of PFAPA syndrome has had variable results. Although thought to reduce the severity of an attack, steroids may have no impact on the frequency of attacks.However, in a review of 94 cases of PFAPA syndrome by Thomas et al,it was thought that glucocorticoids were "highly effective in controlling symptoms." Furthermore, in a review of 28 cases by Padeh et al,9 of 15 patients who were treated with prednisone had complete resolution of symptoms.Federreported that 3 patients treated with oral cimetidine for 1 to 6 months experienced remissions that lasted even after the therapy was discontinued. He cited previous studies in which cimetidine was successfully used to treat common variable hypogammaglobulinemia, infectious mononucleosis, and herpes simplex infections. It was postulated that the agent's immunomodulatory effect was responsible, although thus far the pathophysiologic mechanism of PFAPA syndrome, and thus the mechanism of cimetidine's action, remains unclear. In our case 1, treatment with cimetidine resulted in a brief remission, which lasted until complications required cessation of the therapy. In case 2, the symptoms were not severe; therefore, no medical therapy was required.The value of tonsillectomy for PFAPA syndrome is also unclear. Patient 1 had no noticeable change in the course of her illness after she underwent a tonsillectomy. It is interesting to note that patient 2 had a brief remission from his usual course after surgery, only to have a severe episode 3 months later and then return to the same preoperative pattern of recurrent pharyngitis, lymphadenitis, and fever. Therefore, no lasting benefit was derived from the procedure in either case. The same appears to be true for at least 1 other periodic fever syndrome. In their initial article on hyperimmunoglobulinemia and periodic fever syndrome, van der Meer et alreported that 1 of the 6 patients in their series underwent a tonsillectomy 2 years after onset of the illness, without effect on frequency of episodes. In contrast, Abramson et aldescribed 4 patients with recurrent fever and pharyngotonsillitis that did resolve after tonsillectomy and adenoidectomy. They indicate that although pharyngotonsillitis was not uniformly present in all episodes, adenotonsillectomy was ultimately performed because of adenotonsillar hypertrophy and associated airway obstructive symptoms (3 of 4 patients) or because of a crescendo pattern in the frequency of febrile episodes (1 patient). Although they report multiple similarities between their patients and those described by Marshall et al,the lack of true periodicity in their patients' episodes, as well as the absence of stomatitis or pharyngitis in some of the episodes, makes it unclear if these patients truly had PFAPA syndromes.Some authors have reported success with tonsillectomy for PFAPA syndrome. In a retrospective review of 5 cases of PFAPA syndrome treated with tonsillectomy, Dahn et alreported that all 4 patients who were available for follow-up showed considerable improvement according to the telephone interview with the parents. In a review by Padeh et al,3 patients had complete resolution after tonsillectomy. As Longpoints out in her accompanying editorial, the removal of tonsils may deal only with a disease host site and with not the disease itself.While the role of medical and surgical treatment for PFAPA syndrome is evolving, our patients did not obtain sustained benefit from tonsillectomy. Although many authors have reported success with tonsillectomy for PFAPA syndrome, our limited experience suggests that there may be a subset of patients with this recently described disease entity who may not have long-term benefit from surgery.JLParadiseCDBluestoneRZBachmanEfficacy of tonsillectomy for recurrent throat infection in severely affected children.N Engl J Med.1984;310:674-683.DGWrightDCDaleASFauciSMWolffHuman cyclic neutropenia: clinical review and long-term follow-up of patients.Medicine (Baltimore).1981;60:1-12.HAMajeedMBarakatFamilial Mediterranean fever (recurrent hereditary polyserositis) in children: analysis of 88 cases.Eur J Pediatr.1989;148:636-641.AGedaliaAAdarRGordischerFamilial Mediterrranean fever in children.J Rheumatol Suppl.1992;35:1-9.LMWilliamsonDHullRMehtaWGReevesBHRobinsonPJToghillFamilial Hibernian fever.Q J Med.1982;51:469-480.MAGertzRMPetitJPerraultRAKyleAutosomal dominant familial Mediterranean fever–like syndrome with amylodosis.Mayo Clin Proc.1987;62:1095-1100.JWMvan der MeerJMVossenJRadlHyperimmunoglobulinaemia D and periodic fever: a new syndrome.Lancet.1984;1:1087-1090.JPHDrenthCJHaagsmaJWMvan der Meerand the International Hyper-IgD Study GroupHyperimmunoglobulinaemia D and periodic fever syndrome: the clinical spectrum in a series of 50 patients.Medicine (Baltimore).1994;73:133-144.GSMarshallKMEdwardsJButlerARLawtonSyndrome of periodic fever, pharyngitis, and aphthous stomatitis.J Pediatr.1987;110:43-46.GSMarshallKMEdwardsPFAPA syndrome.Pediatr Infect Dis J.1989;8:658-659.HMFederPeriodic fever associated with aphthous stomatitis, pharyngitis and cervical adenitis.Pediatr Infect Dis J.1989;8:186-187.HWMerchantLPGangarosaABGlassmanRESobelBetamethasone-17-benzoate in the treatment of recurrent aphthous ulcers.Oral Surg Oral Med Oral Pathol.1978;45:870-875.KTThomasHMFederARLawtonKMEdwardsPeriodic fever syndrome in children.J Pediatr.1999;135:15-21.SPadehNBrezniakDZemerPeriodic fever, aphthous stomatitis, pharyngitis, and adenopathy syndrome: clinical characteristics and outcome.J Pediatr.1999;135:98-101.HMFederCimetidine treatment for periodic fever associated with aphthous stomatitis, pharyngitis and cervical adenitis.Pediatr Infect Dis J.1992;11:318-321.JSAbramsonLBGinerJNThompsonPossible role of tonsillectomy and adenoidectomy in children with recurrent fever and tonsillopharyngitis.Pediatr Infect Dis J.1989;8:119-120.KADahnMPGlodeKHChanPeriodic fever and pharyngitis in young children: a new disease for the otolaryngologist?Arch Otolaryngol Head Neck Surg.2000;126:1146-1149.SSLongSyndrome of periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA)—what it isn't: what is it?J Pediatr.1999;135:1-5.Corresponding author: David Roberson, MD, Department of Otolaryngology and Communication disorders, Children's Hospital Boston, 300 Longwood Ave, Boston, MA 02215 (e-mail: david.roberson@tch .harvard.edu).Accepted for publication December 5, 2002. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png JAMA Otolaryngology - Head & Neck Surgery American Medical Association

Utility of Tonsillectomy in 2 Patients With the Syndrome of Periodic Fever, Aphthous Stomatitis, Pharyngitis, and Cervical Adenitis

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American Medical Association
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Copyright 2003 American Medical Association. All Rights Reserved. Applicable FARS/DFARS Restrictions Apply to Government Use.
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2168-6181
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2168-619X
DOI
10.1001/archotol.129.6.670
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12810475
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Abstract

ObjectivesTo review the various causes of period fever in childhood, including the syndrome of periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA), and to examine the value of tonsillectomy in the treatment of PFAPA syndrome.DesignRetrospective case series.SettingUrban and tertiary care referral children's hospital.PatientsTwo patients who underwent tonsillectomy for presumed recurrent adenotonsillitis were later diagnosed as having PFAPA syndrome.InterventionTonsillectomy.Main Outcome MeasureFrequency of PFAPA symptoms before and after tonsillectomy.ResultsNo difference was found in the frequency of PFAPA symptoms after tonsillectomy.ConclusionAlthough a larger series of patients is required, our initial experience suggests that tonsillectomy is not always beneficial for patients with PFAPA syndrome.RECURRENT PHARYNGITIS, frequently accompanied by fever and cervical adenopathy, is a common complaint encountered in any pediatric or pediatric otolaryngology practice. Common causative factors include viral pathogens and bacteria, often Streptococcusspecies. In the latter case, acute episodes typically respond to antibiotic therapy, while tonsillectomy is indicated for patients with frequently recurrent episodes.Also, a variety of noninfectious causes of recurrent pharyngitis and fever have been described, including the "periodic syndromes" cyclic neutropenia, familial Mediterranean fever (FMF), familial Hibernian fever, and hyperimmunoglobulinemia D syndrome.Another periodic syndrome, seldom reported in the otolaryngology literature, is that of periodic fever, cervical adenitis, pharyngitis, and aphthous stomatitis (PFAPA), which was first described by Marshall et alin 1987. Marshall and colleagues identified 12 children who had episodes characterized by the abrupt onset of fever (temperatures as high as 40°C) (100%), malaise (100%), chills (83%), aphthous stomatitis (75%), pharyngitis (75%), and tender cervical lymphadenopathy (67%). Episodes lasted an average of 5 days and occurred at regular 4- to 6-week intervals over the course of several years, usually beginning before the age of 5 years, with the duration of recurrent symptoms from onset to latest follow-up ranging from 1 to 15 years at the time of the report (average duration, 3.9 years). During episodes, the patients did not display any particular susceptibility to infection, and during asymptomatic periods, they were otherwise healthy, normally growing children. The only consistent laboratory abnormalities detected were elevated white blood cell counts (WBCs) and mildly elevated erythrocyte sedimentation rates (ESRs), both of which normalized during asymptomatic intervals. Infectious causes were ruled out by various means, including bacterial and viral cultures, purified protein derivative skin tests, and serologic tests. The results of testing for rheumatologic and autoimmune disorders, including quantitative immunoglobulin levels, antinuclear antibody, anti-DNA antibody, rheumatoid factor, total hemolytic complement, and immune complex levels, were normal or negative.In a subsequent report, Marshall and Edwardsproposed specific diagnostic criteria for this disorder, which they characterized as PFAPA syndrome, after its defining characteristics of periodic fever, aphthous stomatitis, pharyngitis, and adenitis. Their criteria are (1) onset in childhood, usually before the age of 5 years; (2) regularly recurring episodes of fever lasting approximately 5 days, associated with constitutional symptoms and both (a) aphthous stomatitis and/or pharyngitis (with or without cervical adenitis) in the absence of other signs of upper respiratory tract infection and (b) acute inflammatory markers, such as an elevated WBC or ESR; (3) asymptomatic periods, generally lasting less than 10 weeks, or a benign long-term course with no sequelae; (4) exclusion of cyclic neutropenia by serial WBCs before, during, and after symptomatic periods; (5) exclusion of other known periodic syndromes by history, clinical course, and appropriate laboratory studies; and (6) absence of any concurrent immunodeficiency, autoimmune disease, or chronic infection.We describe 2 patients with recurrent pharyngitis, fever, and cervical adenitis refractory to antibiotic therapy and tonsillectomy who were ultimately diagnosed as having PFAPA. We review the diagnostic criteria and treatment for PFAPA, as well as for the other periodic syndromes. Since there is a high likelihood that patients with recurrent pharyngitis will seek otolaryngologic consultation, otolaryngologists should be familiar with the various noninfectious causes of recurrent pharyngitis.REPORT OF CASESCASE 1A 14-year-old white girl presented to our service with a 10-month history of recurrent episodes of cervical lymphadenopathy, fever, and sore throats. She was initially diagnosed as having Epstein-Barr virus (EBV) infection because her serologic tests showed a positive EBV nuclear antigen titer and an elevated level of IgM antibody to EBV viral capsid antigen. Within 1 month of presentation, she underwent excisional biopsy of some persistently prominent right-sided midjugular chain lymph nodes. Pathologic analysis showed chronic inflammatory changes, consistent with nonspecific reactive lymphoid hyperplasia. Over the next few months after biopsy, her lymphadenopathy, which had been predominantly right-sided, became predominantly left-sided. She also continued to have monthly sore throats and fevers lasting 2 to 3 days, which were treated with oral antibiotics.Six months after the patient's initial presentation, a tonsillectomy was performed for presumed recurrent pharyngotonsillitis. For 7 months after tonsillectomy, she continued to have monthly episodes of high fever, cervical lymphadenopathy, and sore throat. She was then symptom free for 2 months, but returned to the office with a persistently enlarged left midjugular lymph node. Fifteen months after her initial presentation, a second excisional biopsy was performed, which again showed reactive lymphoid hyperplasia. After this second biopsy, the patient continued to have recurrent bouts of fever, cervical adenitis, and sore throats. She was seen in consultation by the infectious disease service. Given her protracted course and the negative findings of infectious workup, a diagnosis of PFAPA syndrome was made. She was treated with oral cimeditidine and had no further episodes for 3 months. Unfortunately, she developed urinary retention, which resolved when she stopped taking cimeditidine. Her febrile episodes recurred several months after she discontinued the cimeditidine therapy. At last follow-up, at the age of 16 years, she continued to experience diffuse aphthous stomatitis with accompanying febrile episodes. She otherwise demonstrated no long-term sequelae of her illness.CASE 2A 6-year-old white boy presented to the otolaryngology service with a history of more than 1 year of monthly recurrent fevers (temperatures as high as 38.9°C-40.0°C), which were of sudden onset and lasted 5 to 10 days. With each episode, he demonstrated a diffuse nonexudative pharyngitis, cervical lymphadenopathy (greater on the right side than on the left side), and a variable degree of torticollis or abdominal pain. He was otherwise healthy.Laboratory studies prior to his presentation to our service included multiple WBCs, which were elevated as high as 17.0 × 103/µL during febrile episodes, but normal otherwise. The ESRs were also elevated during episodes, but normalized in asymptomatic periods. Other laboratory studies included multiple throat cultures, serologic testing for EBV and toxoplasmosis, purified protein derivative testing on 2 different occasions, quantitative immunoglobulins, and radiography of the chest, the findings of which were all negative or normal.Each febrile episode was treated with oral antibiotics, but it was unclear if the treatment had any effect on the course of the episodes. Nine months after the patient's symptoms first began, an adenotonsillectomy was performed for presumed recurrent adenotonsillitis. He was well for 3 months after surgery, when he again presented with a severe episode, including sore throat, marked torticollis, and cervical lymphadenopathy. His WBC was 17.0 × 103/µL, and his ESR was 127 mm/h. A computed tomographic scan demonstrated an area of low attenuation in the right retropharyngeal region. The patient was taken to the operating room, where needle aspiration returned a small amount of clear fluid. Gram stain showed gram-positive cocci, but cultures were ultimately negative for organisms. A diagnosis of retropharyngeal phlegmon was made. The patient was treated with 5 days of intravenous cefuroxime therapy, improved, and was discharged home on a regimen of oral cefuroxime. At this point, he was referred to our service for consultation.A magnetic resonance imaging scan of the neck and cervical spine was obtained to rule out an occult source of infection, such as osteomyelitis or a branchial cleft anomaly. An infectious disease consultation was also obtained, and the diagnosis of PFAPA syndrome was made. Because the patient's symptoms were not severe, he has received no further treatment; he continues to have similar recurrent episodes but is otherwise in good health.COMMENTIt is necessary to conclusively rule out other known periodic diseases before making a diagnosis of exclusion, such as PFAPA syndrome. Other diagnoses to consider include cyclic neutropenia, FMF, familial Hibernian fever, hypergammaglobulinemia D, and periodic fever syndrome.Cyclic neutropenia is characterized by recurrent periods of neutropenia due to an abnormality in hematopoiesis.Patients typically present with recurrent fever, malaise, aphthous stomatitis, and cervical adenopathy before the age of 5 years. Cycles occur every 20 to 22 days, with little variation in frequency for any given patient, or between patients, in contrast to the longer cycles experienced by our patients. During symptomatic periods, peripheral neutrophil counts decrease to as low as 0 and remain under 200/µL for 3- to 5-day periods. Furthermore, patients with cyclic neutropenia are susceptible to recurrent infections, such as furunculosis, pneumonia, abscesses, cellulitis, conjunctivitis, and sinusitis, unlike patients with PFAPA syndrome.Several other periodic syndromes have been described that, unlike cyclic neutropenia, are familial. Familial Mediterranean fever, also called recurrent hereditary polyserositis, is an autosomal recessive disorder that is seen primarily in Arabs, Sephardic Jews, and Armenians, and more rarely among Turks, Greeks, and Italians.Manifestations include recurrent episodes of fever, usually beginning before the age of 5 years, of variable frequency (1-40 per year), lasting 2 to 3 days, and associated with one or more of the following: (1) peritonitis, manifested by abdominal pain (90%-95%), (2) arthritis (80%-85%), and (3) pleuritis, manifested by chest pain (20%-40%).Adenopathy, pharyngitis, or aphthous stomatitis is not observed in patients with FMF. Although most patients with FMF do not develop any long-term sequelae, there is a well-documented association with renal amyloidosis and subsequent renal failure in 20% to 60% of affected patients.Although no specific laboratory abnormalities have been identified, patients exhibit significant increases in acute-phase reactants, such as ESR and C-reactive protein, serum haptoglobin, ceruloplasmin, and serum amyloid levels. Rarely, patients will also have an increase in the WBC. These patients experience a marked decrease in the frequency and severity of attacks with oral colchicine therapy. The prominent cervical adenopathy, pharyngitis, and absence of any serosal involvement or family history in our patients strongly argue against FMF as the cause of their recurrent symptoms.A disorder similar to FMF, characterized by recurrent attacks of fever, abdominal pain, tender skin lesions, and myalagias, but demonstrating autosomal dominant inheritance, was identified in an Irish family by Williamson et al.Patients who have this entity, which is called familial Hibernian fever, also demonstrate an increase in WBC and ESR during attacks, have asymptomatic intervals of variable duration, and respond dramatically to the administration of corticosteroids. A similar report from Gertz et aldescribed an American family of German descent with 3 generations afflicted by a disorder quite like FMF, with prominent systemic amyloidosis. In this kindred, inheritance also appeared to be autosomal dominant, and there was no response to colchicine adminstration.In 1984, van der Meer et aldescribed a disorder characterized by recurrent bouts of high, spiking fever accompanied by headache, cervical adenopathy, and occasionally abdominal pain and diarrhea. Most patients developed symptoms before the age of 1 year. Attacks lasted 3 to 7 days and occurred at frequencies varying from weekly to twice per year. Laboratory studies revealed an increase in WBCs and ESRs during symptomatic periods that returned to normal levels between episodes and, most notably, a marked increase in serum IgD levels both during and between episodes.This disorder has been termed hypergammaglobulinemia D and periodic fever syndrome. Its hallmark is the increase in serum IgD levels, a finding that is not present in patients with PFAPA syndrome.Both of our patients clearly meet the diagnostic criteria for PFAPA syndrome. Both had well-defined, regularly recurring episodes of fever, with pharyngitis, significant cervical adenopathy, and transient increases in WBCs and ESRs. It is interesting to note that patient 1 began to exhibit aphthous stomatitis well after the onset of her febrile episodes. Aphthous stomatitis was seen in 75% of the patients in the study of Marshall et al,so its initial absence, as in our patient 2, does not preclude the diagnosis of PFAPA syndrome.Treatment of PFAPA syndrome is controversial. Given the overall benign course of the disorder, no specific treatment might be considered an option. Symptomatic treatment is certainly reasonable in patients with PFAPA syndrome. Aphthous stomatitis can be the most troublesome aspect of PFAPA episodes.A double-blind study reported in the oral surgery literature showed that topical therapy with betamethasone-17-benzoate provided both symptomatic relief and a decrease in the healing time of recurrent aphthous ulcers.In Marshall and colleagues' initial study, treatment with antibiotics or nonsteroidal anti-inflammatory drugs had little effect on symptoms or on the duration or frequency of febrile episodes.Although antibiotic therapy did not have a significant effect on the course of the illness, the occurrence of a retropharyngeal phlegmon in our patient 2 suggests a possible role for prophylactic antibiotic therapy to prevent bacterial superinfection of enlarged cervical lymph nodes.The use of corticosteroids for the treatment of PFAPA syndrome has had variable results. Although thought to reduce the severity of an attack, steroids may have no impact on the frequency of attacks.However, in a review of 94 cases of PFAPA syndrome by Thomas et al,it was thought that glucocorticoids were "highly effective in controlling symptoms." Furthermore, in a review of 28 cases by Padeh et al,9 of 15 patients who were treated with prednisone had complete resolution of symptoms.Federreported that 3 patients treated with oral cimetidine for 1 to 6 months experienced remissions that lasted even after the therapy was discontinued. He cited previous studies in which cimetidine was successfully used to treat common variable hypogammaglobulinemia, infectious mononucleosis, and herpes simplex infections. It was postulated that the agent's immunomodulatory effect was responsible, although thus far the pathophysiologic mechanism of PFAPA syndrome, and thus the mechanism of cimetidine's action, remains unclear. In our case 1, treatment with cimetidine resulted in a brief remission, which lasted until complications required cessation of the therapy. In case 2, the symptoms were not severe; therefore, no medical therapy was required.The value of tonsillectomy for PFAPA syndrome is also unclear. Patient 1 had no noticeable change in the course of her illness after she underwent a tonsillectomy. It is interesting to note that patient 2 had a brief remission from his usual course after surgery, only to have a severe episode 3 months later and then return to the same preoperative pattern of recurrent pharyngitis, lymphadenitis, and fever. Therefore, no lasting benefit was derived from the procedure in either case. The same appears to be true for at least 1 other periodic fever syndrome. In their initial article on hyperimmunoglobulinemia and periodic fever syndrome, van der Meer et alreported that 1 of the 6 patients in their series underwent a tonsillectomy 2 years after onset of the illness, without effect on frequency of episodes. In contrast, Abramson et aldescribed 4 patients with recurrent fever and pharyngotonsillitis that did resolve after tonsillectomy and adenoidectomy. They indicate that although pharyngotonsillitis was not uniformly present in all episodes, adenotonsillectomy was ultimately performed because of adenotonsillar hypertrophy and associated airway obstructive symptoms (3 of 4 patients) or because of a crescendo pattern in the frequency of febrile episodes (1 patient). Although they report multiple similarities between their patients and those described by Marshall et al,the lack of true periodicity in their patients' episodes, as well as the absence of stomatitis or pharyngitis in some of the episodes, makes it unclear if these patients truly had PFAPA syndromes.Some authors have reported success with tonsillectomy for PFAPA syndrome. In a retrospective review of 5 cases of PFAPA syndrome treated with tonsillectomy, Dahn et alreported that all 4 patients who were available for follow-up showed considerable improvement according to the telephone interview with the parents. In a review by Padeh et al,3 patients had complete resolution after tonsillectomy. As Longpoints out in her accompanying editorial, the removal of tonsils may deal only with a disease host site and with not the disease itself.While the role of medical and surgical treatment for PFAPA syndrome is evolving, our patients did not obtain sustained benefit from tonsillectomy. Although many authors have reported success with tonsillectomy for PFAPA syndrome, our limited experience suggests that there may be a subset of patients with this recently described disease entity who may not have long-term benefit from surgery.JLParadiseCDBluestoneRZBachmanEfficacy of tonsillectomy for recurrent throat infection in severely affected children.N Engl J Med.1984;310:674-683.DGWrightDCDaleASFauciSMWolffHuman cyclic neutropenia: clinical review and long-term follow-up of patients.Medicine (Baltimore).1981;60:1-12.HAMajeedMBarakatFamilial Mediterranean fever (recurrent hereditary polyserositis) in children: analysis of 88 cases.Eur J Pediatr.1989;148:636-641.AGedaliaAAdarRGordischerFamilial Mediterrranean fever in children.J Rheumatol Suppl.1992;35:1-9.LMWilliamsonDHullRMehtaWGReevesBHRobinsonPJToghillFamilial Hibernian fever.Q J Med.1982;51:469-480.MAGertzRMPetitJPerraultRAKyleAutosomal dominant familial Mediterranean fever–like syndrome with amylodosis.Mayo Clin Proc.1987;62:1095-1100.JWMvan der MeerJMVossenJRadlHyperimmunoglobulinaemia D and periodic fever: a new syndrome.Lancet.1984;1:1087-1090.JPHDrenthCJHaagsmaJWMvan der Meerand the International Hyper-IgD Study GroupHyperimmunoglobulinaemia D and periodic fever syndrome: the clinical spectrum in a series of 50 patients.Medicine (Baltimore).1994;73:133-144.GSMarshallKMEdwardsJButlerARLawtonSyndrome of periodic fever, pharyngitis, and aphthous stomatitis.J Pediatr.1987;110:43-46.GSMarshallKMEdwardsPFAPA syndrome.Pediatr Infect Dis J.1989;8:658-659.HMFederPeriodic fever associated with aphthous stomatitis, pharyngitis and cervical adenitis.Pediatr Infect Dis J.1989;8:186-187.HWMerchantLPGangarosaABGlassmanRESobelBetamethasone-17-benzoate in the treatment of recurrent aphthous ulcers.Oral Surg Oral Med Oral Pathol.1978;45:870-875.KTThomasHMFederARLawtonKMEdwardsPeriodic fever syndrome in children.J Pediatr.1999;135:15-21.SPadehNBrezniakDZemerPeriodic fever, aphthous stomatitis, pharyngitis, and adenopathy syndrome: clinical characteristics and outcome.J Pediatr.1999;135:98-101.HMFederCimetidine treatment for periodic fever associated with aphthous stomatitis, pharyngitis and cervical adenitis.Pediatr Infect Dis J.1992;11:318-321.JSAbramsonLBGinerJNThompsonPossible role of tonsillectomy and adenoidectomy in children with recurrent fever and tonsillopharyngitis.Pediatr Infect Dis J.1989;8:119-120.KADahnMPGlodeKHChanPeriodic fever and pharyngitis in young children: a new disease for the otolaryngologist?Arch Otolaryngol Head Neck Surg.2000;126:1146-1149.SSLongSyndrome of periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA)—what it isn't: what is it?J Pediatr.1999;135:1-5.Corresponding author: David Roberson, MD, Department of Otolaryngology and Communication disorders, Children's Hospital Boston, 300 Longwood Ave, Boston, MA 02215 (e-mail: david.roberson@tch .harvard.edu).Accepted for publication December 5, 2002.

Journal

JAMA Otolaryngology - Head & Neck SurgeryAmerican Medical Association

Published: Jun 1, 2003

References