PERIODIC FEVER/OTITIS MEDIA
| DIAGNOSTIC APPROACH TO PERIODIC FEVERS —Henry M. Feder, Jr, MD, Professor of Pediatrics and
Family Medicine, University of Connecticut Health Center, Farmington, and Connecticut Children’s Medical
Center, Hartford
|
 | Fever 1: 18-mo-old boy admitted to emergency department (ED); had 12 hr of fever (on presentation, temperature
105° F); child listless but otherwise physical examination normal; white blood cell count (WBC) slightly high
(20500 µL); C-reactive protein (CRP) elevated (problem not necessarily bacterial); blood culture pending; no
antibiotics administered; in 4 days, fever gone
|
| Fever 2: same patient now 19 mo of age; 102° F fever for 4 hr; otitis media (OM) ruled out; no treatment; in 2 days,
fever gone
|
| Fever 3: presentation ≈1 mo later; 102° F to 104° F temperature 3 days during ski trip; fever resolved without intervention;
clinical presentation normal; no one else in family sick when child sick (problem not viral infection);
no unusual family history; slight prodrome of not eating before onset of fever (nonspecific); speaker
orders laboratory studies when he expects positive result (eg, test for Salmonella during community outbreak);
CRP not helpful
|
| Fever 4: presentation 28 days later; 4 hr of temperature near 102° F; physical examination normal; no aphthous stomatitis
or pharyngitis (with fever, red tonsils normal; Rapid Strep A Test useful); adenitis (shoddy nodes; normal);
full work-up performed (WBC and erythrocyte sedimentation rate [ESR] normal, but CRP elevated; chest
x-ray normal; liver function test; quantitative immunoglobulins [IgA, IgM, IgG]); next day, fever near 104° F;
negative laboratory studies (blood, throat, and urine cultures)
|
| Case 2: adolescent boy, 15 yr of age, had seen many doctors; periodic fever since 2 yr of age; severe aphthous stomatitis;
patient losing weight and having trouble eating; severe sore throats; tonsils not normal (erythema with
white areas; when sampled for culture, exudate did not come off); glands in neck tender; multiple hospitalizations;
Mycoplasma in saliva (elimination of organism made no difference); ESR elevated (sometimes normal); WBC elevated
(sometimes normal); immunoglobulin assay normal; periodic fever over 13 yr (130 episodes, each lasting 5-
7 days); in past, fever lysed with steroids (now mother refuses steroid treatment)
|
| Syndrome of periodic fever, pharyngitis, and aphthous stomatitis (Marshall et al, 1987): initial description
of new syndrome; 12 children; fevers beginning at <5 yr of age, persist 2 or 3 wk, and resolve spontaneously
within 7 days, regardless of treatment; fevers usually >103° F (average 104° F; maximum 105.6° F); average
duration 5 days; recurrence-interval average, 4.5 wk (range, 2-9 wk); associated signs and symptoms—aphthous
stomatitis (75%); pharyngitis (75%); cervical adenitis (67%); 50% had headache, vomiting, and abdominal pain
with fevers; no rashes or joint problems; if severe arthralgias, joint swelling, or rashes present, differential diagnosis
another group of conditions; during episode, WBC and ESR may be elevated (CRP may be better indicator); patients
normal between episodes; no sequelae; fever resolves with short course of prednisone (40 mg/day)
|
| Behçet’s syndrome (case): patient had 1 major (>1 cm) and 2 minor aphthous ulcers; lip sometimes swollen; pain
made eating difficult; 2 mo of aphthous stomatitis with fevers; patient lost weight; fever and periodicity not characteristic
(distinguishable from periodic fever associated with aphthous stomatitis, pharyngitis and cervical adenitis
[PFAPA])
|
| Cimetidine (off-label use in treatment of new syndrome)
|
| Case: child previously prescribed cimetidine (Tagamet) for mononucleosis; anecdotally, cimetidine helpful (H2 -
blockers have mild immune-modulating properties); White and Ballow 1985—common variable immunodeficiency
(patients with low immunoglobulins responded to cimetidine; results reproducible); treatment—mother
refused steroids; child felt better with cimetidine
|
| Feder 1989: named syndrome (PFAPA); child with PFAPA given cimetidine (episodes stopped); however, PFAPA
known to resolve spontaneously
|
| Feder 1992: 2 more patients with PFAPA; in 3 of 3 cases, cimetidine effective; caveat—PFAPA can resolve spontaneously
after 4 or 5 episodes; duration ≥1 yr; speaker has seen duration of 13 yr, but PFAPA does not persist
into adulthood (other forms of periodic fever lifelong); criticism—further studies indicate that cimetidine works
sometimes (but usually does not)
|
| Periodic fever syndrome in children (Thomas KT et al, 1999): 94 patients with suspected PFAPA; inclusion
criteria aphthous stomatitis, pharyngitis, or adenitis; fever episodes lasted ≈4.5 days, with recurrences at ≈28 days (1
per mo); those that resolved after 4 episodes lasted ≈4.5 yr; patients outgrow (problem starts at 4 yr of age, resolves
by 8 yr of age); frequent aphthous stomatitis (70%); frequent pharyngitis (72%); frequent adenitis (88%); headache
(60%); abdominal pain (49%); treatment—Tagamet used in 30 patients (10 responded); fever lysed with 1 or 2
doses of prednisone (1 mg/kg per dose); problem—fever may lyse anyway (usually lasts 5 days, some 2 days); diagnostic
marker—steroids effectively lysed fever; role of tonsillectomy—11 of 94 patients had tonsillectomies (tonsils
large and inflamed during episodes, so otolaryngologists routinely excised them; in 9 of 11 patients, episodes
stopped with tonsillectomy (in 2 of 11, number of episodes, severity of fever, and overall symptoms decreased); with
steroid therapy only, fever resolves, but cyclic problem recurs
|
| Periodic fever, aphthous stomatitis, pharyngitis, and adenopathy syndrome (Padeh et al, 1999): familial
Mediterranean fever (FMF) (as opposed to PFAPA)—usually begins at >10 yr of age; steroids have no effect;
patients with PFAPA lack marker gene for FMF; in patients with FMF, colchicine reduces frequency of
attacks
|
| Herpetiform aphthous stomatitis: cluster of aphthous ulcers seen in PFAPA (not blisters; distinguishable from
herpes simplex virus [HSV]); HSV lesions seen at junction of skin and lip (not inside mouth; exceptions rare)
|
| Kawasaki disease: also presents with cervical adenopathy, but nodes lack periodicity seen in PFAPA
|
| Streptococcal pharyngitis: clinical signs similar, but cultures consistently negative in patients with PFAPA
|
| Genetic testing: expensive; generally not indicated in work-up of PFAPA (genetic conditions distinguishable
based on clinical characteristics)
|
| Cyclic neutropenia: in cyclic neutropenia, timing exact (fever cycle recurs every 19 to 21 days; in PFAPA, cycles
>21 days [with rare exceptions], and less exact); mucositis (as opposed to aphthous stomatitis) and bacterial infections
suggest cyclic neutropenia (not PFAPA; hypothesis that high level of interferon may be protective); in cyclic
neutropenia, absolute neutrophil count (ANC) usually low-normal (during episode, count close to zero); episodes
last 3 to 6 days; associated infections include sinusitis, pneumonia, peritonitis, and bacteremia; children with low
ANC respond to erythropoietin (Epogen); summary—cyclic neutropenia diagnosed clinically (cycles exact and evidence
of bacterial infection present)
|
| Behçet’s syndrome vs PFAPA: aphthous ulcers in mouth larger and heal with scarring; patients also get genital
ulcers (fever rare and not cyclic); patients older (PFAPA usually presents at <5 yr of age); genetic predisposition
identified; can be devastating illness; nonblistering lesions (distinguishable from those of HSV)
|
| Genetic factors: identified in FMF, hyperimmunoglobulin-emia D with periodic fever syndrome (HIDS), tumor
necrosis factor (TNF) receptor-associated periodic syndrome (TRAPS; rare); genetic studies—expensive (cost of 3
tests ≈$3000); speaker avoids (conditions distinguishable from PFAPA based on clinical presentation)
|
| Hyperimmunoglobulinemia D syndrome: closely resembles PFAPA; HIDS first described in small group of
patients from Netherlands; potential family history (not true for PFAPA)
|
| Familial Mediterranean fever: case—patient presented with severe abdominal pain, 103° F fever, and crying;
father has FMF; presentation—fever and chest or abdominal pain, or fever and rash that looks like cellulitis; duration
of episode 6 hr to 4 days; genetic test results positive; treatment colchicine (also used to treat aphthous
stomatitis); patients do not respond to prednisone; family history specific; fever lacks periodicity seen in PFAPA
(FMF may have 2 or 3 episodes/year)
|
| More about HIDS: fever 4 to 6 days; usually begins at <1 yr of age; symptoms include aphthous stomatitis, cervical
adenitis, and abdominal pain; look for family history or Dutch ancestry; IgD level may not be elevated early in
course of illness (elevated IgA another marker); like FMF, and unlike PFAPA, joint involvement and rash
|
| Diagnosis of TRAPS (also known as, familial Hibernian fever): first described in 1982; episodes usually 14
days (longer than PFAPA); rash and severe muscle pain; periorbital edema; family history (mutation in TNF1 gene
identified)
|
| Traumatic aphthous lesions: usually on cheeks under fixed gingiva (not hard palate, nonfixed mucosa, or top of
tongue); traumatic lesions (due to, eg, orthodontic appliances or teething) not aphthous stomatitis
|
| HSV infection: lesions recur at junction of skin and lips; no fever with outbreaks; herpes antibodies present (some
patients with PFAPA have them, some do not); treatment of recurrent herpes labialis—significant placebo effect;
prophylactic administration of oral acyclovir best strategy to prevent recurrences; stress common trigger (treatment
few days before potentially inciting event can prevent 90% of outbreaks); valacyclovir and famciclovir (Famvir)
also effective; results with topical therapy, eg, penciclovir, poor (by time lesions appear, too late); use oral acyclovir
prophylactically; by definition, lesions outside mouth not aphthous stomatitis
|
| Recurrent aphthous stomatitis
|
| Diagnosis: without fever (ie, not associated with PFAPA)—runs in families; immunologic and microbiologic implications
(patients infected by own flora); nutritional implications (in some individuals, eating tomatoes causes
aphthous stomatitis); get history; associated with PFAPA—nonkeratinized, freely movable mucosa; minor lesions
<1 cm (major >1 cm); sometimes can scar; “herpetiform” aphthous stomatitis refers to clustering and unrelated
to HSV infection
|
| Treatment: topical amoxicillin not effective (once lesions appear, too late); colchicine (used to treat FMF); thalidomide
(immune modulating agent; causes severe birth defects); over-the-counter medications (eg, Tagamet HB,
zinc lozenges); avoid—sodium lauryl sulfate (foaming agent in some toothpaste products; anecdotal link to aphthous
stomatitis); calcium channel blockers (not indicated for children); nonsteroidal anti-inflammatory drugs
(NSAIDS; rare cause); topical steroid therapy—dry mucosa and apply clobetasol (Temovate) 4 times/day; steroid
mouthwash—consider dexamethasone (Decadron; some may be absorbed) or triamcinolone; steroids used
short-term for severe cases
|
| Case 1 revisited: 4th fever (temperature 104° F); many laboratory tests (blood, throat, and urine cultures performed);
consider genetic studies or referral to infectious disease specialist; for patient 3 yr of age, consider 1 tsp
oral prednisone to lyse fever (if fever recurs and responds to same therapy, diagnosis PFAPA); as alternative to steroids,
some parents treat symptoms of PFAPA with acetaminophen (Tylenol) or ibuprofen (Motrin) and wait for
patient to outgrow; consider tonsillectomy
|
| A “WAIT-AND-SEE” APPROACH TO MANAGING ACUTE OTITIS MEDIA —Jerome O. Klein, MD, Professor
of Pediatrics, Boston University School of Medicine, Boston, MA
|
| Article: Wait-and-see prescription for the treatment of acute otitis media: a randomized controlled trial (Spiro et al,
2006)
|
| Author’s conclusion: wait-and-see approach substantially reduced unnecessary use of antibiotics in children with
acute otitis media (AOM) seen in emergency department (ED), and may be alternative for routine use of antimicrobials
for treatment of such children
|
| Methods: randomized controlled trial of 283 children 6 mo to 12 yr of age diagnosed with AOM in ED; patients assigned
to—standard prescription (SP; almost all given amoxicillin) or wait and see prescription (WASP; parents
asked not to fill prescription unless child not better, or if worse, in 48 hr); exclusions—patients too toxic, or treated
with antibiotics in previous 7 days, or no reliable medical access; research assistant—conducted telephone interviews
at various intervals after enrollment; outcomes—filling of prescription; parent report of clinical course
|
| Results: 87% in SP group received antibiotics (38% in WASP group, average time 2 days); within WASP group, no
difference in subsequent fever, otalgia, or office visits, whether prescription filled or not; diarrhea more common in
group that filled more prescriptions for amoxicillin
|
| Limitations of study: no validation of diagnosis beyond judgment of ED physician; no subsequent clinical examination
by physician (end point parent’s perceived need for antibiotic and response to telephone survey); of 776 patients
eligible for study, two thirds not enrolled (of those, parents or physicians chose not to enroll 185 children to
avoid possible randomization to WASP group); median age 3.4 yr (only 28% of children in trial <2 yr of age);
mean temperature at triage 37° C (98.6° F) (only 22% of children ≥38° C [100.4° F])
|
| Speaker’s insights: wait-and-see approach useful in reducing antibiotic treatment of AOM, but population very select;
child most likely to benefit >2 yr of age with mild disease (ie, afebrile); study did not evaluate severe disease
(many not enrolled because of physician or parent preference; study that incorporates children with severe signs of
disease may not be possible)
|
| Television news report about study: 2 mothers in park asked if they would agree to withhold antibiotics from
child when he or she has AOM (answer “no”)
|
Suggested Reading
Arav-Boger R, Spirer Z: Periodic syndromes of childhood. Ad Pediatr 44:389, 1997; Condemi JJ: The autoimmune
diseases. JAMA 258:2920, 1987; Drenth JP et al: Mutations in the gene encoding mevalonate kinase cause hyper-IgD
and periodic fever syndrome. International Hyper-IgD Study Group. Nat Genet 22:178, 1999; Feder HM Jr:
Cimetidine treatment for periodic fever associated with aphthous stomatitis, pharyngitis and cevical adenitis. Pediatr Infect
Dis J 11:318, 1992; Feder HM Jr: Periodic fever, aphthous stomatitis, pharyngitis, adenitis: a clinical review of a
new syndrome. Curr Opin Pediatr 12:253, 2000; Ghate JV, Jorizzo JL: Behcet’s disease and complex aphthosis. J
Am Acad Dermatol 40:1, 1999; Grose C et al: Children with hyperimmunoglobulinemia D and periodic fever syndrome.
Pediatr Infect Dis J 15:72, 1996; Marshall GS et al: PFAPA syndrome. Pediatr Infect Dis J 8:658, 1989;
Marshall GS et al: Syndrome of periodic fever, pharyngitis, and aphthous stomatitis. J Pediatr 110:43, 1987; Meyerhoff
J: Familial Mediterranean fever: report of a large family, review of the literature, and discussion of the frequency
of anyloidosis. Medicine (Baltimore) 59:66, 1980; Padeh S et al: Periodic fever, aphthous stomatitis,
pharyngitis, and adenopathy syndrome: clinical characteristics and outcome. J Pediatr 135:98, 1999; Ship JA: Recurrent
aphthous stomatitis. An update. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 81:141, 1996; Spiro DM et
al: Wait-and-see prescription for the treatment of acute otitis media: a randomized controlled trial. JAMA 296:1235,
2006; Thomas KT et al: Periodic fever syndrome in children. J Pediatr 135:15, 1999; White WB, Ballow M:
Modulation of suppressor-cell activity by cimetidine in patients with common variable hypogammaglobulinemia. N
Engl J Med 312:198, 1985; Whitley RJ et al: Herpes simplex viruses. Clin Infect Dis 26:541, 1998; Wright DG et
al: Human cyclic neutropenia: clinical review and long-term follow-up of patients. Medicine (Baltimore) 60:1, 1981.
Educational Objectives
| The goal of this program is to improve management of periodic fever syndromes and otitis media. After hearing and
assimilating this program, the clinician will be better able to:
|
| 1. Recognize clinical features of the syndrome of periodic fever associated with aphthous stomatitis, pharyngitis,
and cervical adenitis (PFAPA).
|
| 2. Choose appropriate therapy for managing PFAPA.
|
| 3. Perform a differential diagnosis of periodic fever syndromes.
|
| 4. Diagnose and manage conditions that present with recurrent oral lesions but without fever.
|
| 5. Evaluate the merits of a recent article about delayed treatment of acute otitis media.
|
Faculty Disclosure
In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty members to disclose
relevant financial relationships within the past 12 months that might create any personal conflicts of interest. Any
identified conflicts were resolved to ensure that this educational activity promotes quality in health care and not a proprietary
business or commercial interest. For this program, the faculty reported nothing to disclose.
Acknowledgements
Dr. Feder was recorded at the Cape Cod Conference on Pediatrics 2006, presented August 4-6, 2006, in Hyannis,
MA, by Nemours Children’s Clinic, Jacksonville, FL; Dr. Klein was recorded at Current Concepts in Pediatric Infectious
Diseases, presented November 3-4, 2006, in Boston, MA, by Children’s Hospital Boston and Boston Medical
Center. The Audio-Digest Foundation thanks Drs. Feder and Klein, and the meeting sponsors, for their cooperation in
the production of this program.
|
