periodic fevers in children walter dehority, m.d., msc
TRANSCRIPT
Periodic Fevers in Children
Walter Dehority, M.D., MSc.
Outline• 1.) Introduction• 2.) The Major Players
– A.) PFAPA– B.) Hyper IgD Syndrome– C.) Familial Mediterranean Fever Syndrome– D.) TRAP Syndrome– E.) Cyclic Neutropenia– F.) Recurrent Viral Illnesses
• 3.) Other Periodic Fever Syndromes• 4.) Key Historical Questions• 5.) Key Physical Examination Features• 6.) Key Laboratory Features• 7.) Practical Approach to Diagnosing a Child with Periodic Fevers• 8.) Diagnosis• 9.) Treatment of the Child with Periodic Fevers
1.) Introduction
• Many consequences of periodic fevers in children– Unnecessary antibiotics– Missed school– Missed work for parents– Cost of repeated medical visits– Parental and physician anxiety
1.) Introduction
• The presentation of febrile episodes (severity, duration, frequency, associated symptoms) may vary greatly, but most patients with such syndromes are completely well in between episodes
2.) The Major Playersa.) PFAPA Syndrome
Review of 6 Case Series and 395 Patients• Periodic Fevers– Typically every 3-6 weeks and lasting 3-7 days at a
time (mean duration 4.1 to 5.3 days)• Aphthous stomatitis (38-75%)• Pharyngitis (75-100%)– Often no exudate
• Adenitis (61-100%)– Cervical– No fluctuance
Marshall, et al. J Pediatr. 1987;110:43-46Thomas, et al. J Pediatr. 1999;135:15-21Padeh, et al. J Pediatr. 1999;135:98-101Gattorno, et al. Pediatr. 1009;124:e721-28Feder, et al. Acta Paediatr. 2010;99:178-184Tasher, et al. Acta Paediatr. 2008;97:1090-1092
Presentation of PFAPA: 6 Case Series, 395 PatientsSymptom Marshall,
et alThomas, et al
Padeh, et al Tasher, et al
Gattorno, et al
Feder, et al
Mean duration fever (days)
--- 4.8 4.8 5.3 4.5 4.1
Pharyngitis % 75 65 100 96 84 85
Cervical LAD %
67 77 100 61 84 62
Apthous stomatitis %
75 67 68 39 59 38
Headache % --- 65 18 46 41 44
Arthralgia % --- --- 11 --- 44 ---
Diarrhea % --- 30 000 13 29 ---
Abdominal Pain %
--- 45 18 65 53 41
Rash % --- 15 --- 4 22 ---
2.) The Major Playersa.) PFAPA Syndrome
• Parents often can tell when an episode is set to begin
• Periodicity may be strikingly regular, down to the day
2.) The Major Playersa.) PFAPA Syndrome
• Average age of onset around 2-3 years • May see ‘atypical’ symptoms occasionally
occurring with the fevers– Abdominal pain– Emesis– Diarrhea
Caorsi, et al. Curr Opin Rheum. 2010;22:579-84
2.) The Major Playersa.) PFAPA Syndrome
• Self-limited illness– Average duration of illness in a recent long-term
follow-up study reported to be 6.3 years– No sequelae known
• The period between fevers typically lengthens as PFAPA begins to resolve
Wurster, et al. J Pediatr. 2011;159:958-964
2.) The Major Playersb.) Hyper IgD Syndrome
• Normally begins in first year of life (>90%)• 4-6 days of fever• Normally develop abdominal pain and/or
emesis (>90%), cervical lymphadenopathy (90%) with fevers
• Splenomegaly common (1/3 of patients)• May see arthritis (80%), rashes (2/3) and oral
ulcers (50%)Drenth, et al. NEJM. 2001. 345;24:1748-57Van der Hilst, et al. Medicine. 2008;87(6):301-10
2.) The Major Playersb.) Hyper IgD Syndrome
• Autosomal recessive– Affected siblings may be present
Drenth, et al. NEJM. 2001;345(24):1748-57
2.) The Major Playersb.) Hyper IgD Syndrome
• Genetic diagnosis available • IgD levels may be elevated, but this is an
inconsistent finding (may be normal in younger children, and retrospective data suggests poor correlation with disease)
• Elevation of IgA and IgD levels more consistent with the diagnosis, particularly if a genetic diagnosis is present as well
Ammouri, et al. Rheumatoloy. 2007;46:1597-1600Va der Hilst, et al. Medicine. 2008;87(6):301-10Drenth, et al. NEJM. 2001;345(24):1748-57
2.) The Major Playersb.) Hyper IgD Syndrome
• Frequency of attacks decreases as children age• As they get older, individuals may go months
or years without attacks
Ammouri, et al. Rheumatoloy. 2007;46:1597-1600
2.) The Major Playersc.) Familial Mediterranean Fever
• Specific ethnic background not required for diagnosis
• Short attacks (often only 1-2 days)• Arthritis (75% with a non-migratory
monoarthritis), peritonitis/abdominal pain (95%---most of whom present with an acute abdomen), pleuritis frequently present
• Onset may be late in life (adolescence or beyond)
Drenth, et al. NEJM. 2001;345(24):1748-57
2.) The Major Playersc.) Familial Mediterranean Fever
• Erysipelas like lesions on shins/feet in 7-40%
2.) The Major Playersd.) TRAP Syndrome
• TNF-Receptor Associated Periodic Syndrome• Also referred to as Familial Hibernian Fever
2.) The Major Playersd.) TRAP Syndrome
• May have prolonged attacks that last for weeks
• Migratory myalgias/muscle tightness in 80%• Abdominal pain, emesis, diarrhea frequently• Conjunctivitis, periorbital edema and chest
pain frequently seen• 60% with erythematous macules• Arthralgias common
Drenth, et al. NEJM. 2001;345(24):1748-57
2.) The Major Playerse.) Cyclic Neutropenia
• Monocyte and neutrophil values oscillate in opposite phase to one another every 21 days (90% of patients)
• Peak ANC may be lower than normal• Recurrent oral ulcers and infections,
frequently in concert with recurrent neutropenia
Horwitz, et al. Blood. 2007;109:1817-1824
2.) The Major Playerse.) Cyclic Neutropenia
• Neutropenia may precede symptoms by several days
• Neutropenia typically lasts 3-5 days• Onset typically under 1 year of age• Bacterial infections of skin are common
Lubitz, et al. Pediatr Dermatol. 2001;18(5):426-432
2.) The Major Playersf.) Recurrent Viral Infections
• Does the child frequently have rhinorrhea, cough, etc during febrile episodes?
• Do they attend daycare?• Are concurrent ill contacts frequently present
in the household during the child’s febrile episodes?
3.) Key Historical Features: Questions to Ask
• How often do the fevers occur?– Is there any regularity/periodicity to them?– e.g. every 4 weeks vs. every 4-6 weeks vs. every 3
weeks vs. no pattern
3.) Key Historical Features: Questions to Ask
• How old was the child when the episodes began?– Under or over 1 year of age?
• How long do the fevers last when they occur?– Several days vs. weeks or more
3.) Key Historical Features: Questions to Ask
• How high are the fevers and are they controllable with antipyresis?
• Any associated signs/symptoms– Particular attention to oral ulcers, cervical adenitis,
pharyngitis, arthritis, abdominal pain, emesis/diarrhea, conjunctivitis
• Any concerning concurrent systemic findings?– e.g. weight loss, loss of developmental milestones
3.) Key Historical Features: Questions to Ask
• Any family history of recurrent fevers, rheumatological or immunological disorders?
• Any treatments attempted (e.g. antibiotics, steroids) in the past, and did they work?
• Do household members get fevers at the same time?
3.) Key Historical Features: Questions to Ask
• Is the child otherwise well when not having a febrile episode?
4.) Key Physical Examination Features
• Verification of fever• Oral ulcers• Lymphadenopathy• Rashes• Conjunctivitis • Arthritis • Pharyngitis
5.) Key Laboratory Features
• Are inflammatory markers elevated (e.g. CRP, ESR, WBC, platelets) during febrile episodes?
• Do inflammatory markers normalize when afebrile?
6.) Other Periodic Fever Syndromes
• Neonatal onset multi-system inflammatory disease
• Muckle-Wells syndrome• Familial cold-urticaria• Majeed syndrome
7.) Practical Approach to the Child with Periodic Fevers
• 1st---verify the presence of fever– How is the temperature being assessed? How
frequently?• 2nd---determine the frequency/periodicity of
the episodes
Frequency/Periodicity of Various Periodic Fever Syndromes
Frequency of Episodes
PFAPA Cyclic Neutropenia
FMF HIDS TRAPS
Range q 3-6 weeks q 2-8 weeks q 3-4 months
q 4-8 weeks q weeks to years
‘Classic’ q 28 days q 21 days (90%)
None None None
7.) Practical Approach to the Child with Periodic Fevers
• 3rd---Determine the length of episodes
Duration of Febrile Episodes in Various Periodic Fever Syndromes
PFAPA Cyclic Neutropenia
FMF HIDS TRAPS
3-5 days 5-7 days 1-3 days 3-7 days 2 days-weeks
7.) Practical Approach to the Child with Periodic Fevers
• 4th---Determine if the child is well in between episodes and gaining weight– If not (e.g. continuing malaise, systemic
symptoms, poor appetite/activity levels), more concern over a serious, systemic process (e.g. rheumatologic/oncologic disorder)
7.) Practical Approach to the Child with Periodic Fevers
• 5th---Assess via history and examination for syndrome specific physical examination findings
Examination Findings Associated with Various Periodic Fever Syndromes
Finding PFAPA Cyclic Neutropenia
FMF HIDS TRAPS
Oral Ulcers Yes Yes No Yes No
Pharyngitis Yes No No No No
Cervical LAD Yes No No Yes No
Rash No No Yes Yes Yes
Splenomegaly No No No Yes No
Periorbital edema
No No No No Yes
Pseudocellulitis No No No No Yes
7.) Practical Approach to the Child with Periodic Fevers
• 6th---Have the family keep a fever diary– Record dates febrile episodes began and end– Record associated symptomatology (if any)
7.) Practical Approach to the Child with Periodic Fevers
• 7th---Measure inflammatory markers while febrile and when recovered– If markers not elevated with fevers, may not be
true febrile episodes– If markers do not normalize when afebrile, more
concern over a serious, systemic disorder (e.g. rheumatologic/oncologic)
Flowchart for the Initial Evaluation of a Child with Periodic Fevers and No Suspicion of Recurrent Viral Infections
Verify Fever
Well in-between Episodes with no weight loss and normal inflammatory markers?
Age onset <1 year?
Assess Frequency of Fever
Evaluate for more serious etiology (e.g. Rheumatologic, Oncologic)
Yes Cyclic Neutropenia
Hyper IgD Syndrome
Findings Fit?Neutropenia q 3 weeks,Fevers q 21 days, oral ulcers,Recurrent bacterial infections
Abdominal pain, rash,diarrhea, splenomegaly
No
Findings Fit? Findings Fit?Regular Irregular
q 21 days
q 3-6 weeks
q 4-8 weeks
q 4-8 weeks
Weeks to months
Weeks to years
Cyclic Neutropenia
PFAPA
Hyper IgD Syndrome
Neutropenia q 3 weeks,fevers q 21 days, oral ulcers,recurrent bacterial infectionsPharyngitis, cervical adenitis, oral ulcers
Abdominal pain, rash, diarrheasplenomegaly
Abdominal pain, rash, diarrhea,splenomegaly
Abdominal pain, rash, arthritis
Abdominal pain, rash, periorbitaledema, arthritis
Hyper IgD Syndrome
FMF
TRAPS
No
Yes
7.) Practical Approach to the Child with Periodic Fevers:Hyper IgD Syndrome/PFAPA/Cyclic Neutropenia
• Overlap in presentation– All may cause • Recurrent fevers every 3 weeks or so• Fevers lasting 3-7 days• Oral ulcers
7.) Practical Approach to the Child with Periodic Fevers:Hyper IgD Syndrome/PFAPA/Cyclic Neutropenia
• 33/42 patients with Hyper IgD syndrome fit criteria for PFAPA in a recent study in Pediatrics
Gattorno, et al. Pediatr. 2009;124(4):e721-9
Hyper IgD Syndrome/PFAPA/Cyclic Neutropenia---Differentiating Features
Variable PFAPA Cyclic Neutropenia Hyper IgD Syndrome
Age at onset 2 years <1 year in 90% <1 year often
Rash No No Often
Recurrent Bacterial Infections
No Yes No
Abdominal Pain/Diarrhea
Occasionally No Frequent
Periodicity 3-6 weeks, normally 4 weeks
21 days >90% of time
4-8 weeks
7.) Practical Approach to the Child with Periodic Fevers:Red Flag Signs
• Rash, arthritis, abdominal pain, chest pain, conjunctivitis– May signal FMF, HIDS, TRAPS• More serious and potentially treatable causes of
periodic fevers than PFAPA
• PFAPA may cause abdominal pain/emesis, etc---but if these are present, would pursue testing for other syndromes
7.) Practical Approach to the Child with Periodic Fevers:Red Flag Signs
• Gattorno, et al– 395 children with periodic fevers– Children with inheritable causes of periodic fever
syndrome (i.e. not PFAPA) more likely to have abdominal pain and diarrhea (p<0.001), emesis (p=0.006) and rash/arthralgia (p=0.01)
– Those without inheritable causes of periodic fever were more likely to have exudative pharyngitis (p=0.01)
Gattorno, et al. Pediatr. 2009;124(4):e721-9
7.) Practical Approach to the Child with Periodic Fevers:Red Flag Signs
• Gattorno, et al– Periodicity of fevers did not distinguish between
causes of periodic fevers well (e.g. Hyper IgD syndrome and PFAPA)
Gattorno, et al. Pediatr. 2009;124(4):e721-9
8.) Diagnosis
• PFAPA– Clinical diagnosis– Suggested criteria may not be specific enough:• e.g.---onset <5 yrs old and 1/3 clinical criteria (cervical
LAD, pharyngitis, aphthous stomatitis) with every episode• 33/42 patients with Hyper IgD syndrome fit this clinical
criteria
Gattorno, et al. Pediatr. 2009;124(4)
8.) Diagnosis
• PFAPA– May need to exclude other syndromes,
particularly if abdominal pain/emesis is present– Of note• Patients need not have all 3 symptoms with every fever• May have fevers with none of the symptoms from time
to time
8.) Diagnosis
• Cyclic Neutropenia– Document neutropenia– Best accomplished with 2 CBC with differentials a
week for 6 weeks (neutropenia cycles every 3 weeks, but may be missed if assessed only during one 3 week period or once per week)
– Practically, one CBCD per week is probably feasible to start with
– Genetic testing
8.) Diagnosis
• Hyper IgD Syndrome– Genetic testing – IgD and IgA levels
8.) Diagnosis
• Familial Mediterranean Fever– Genetic testing– Clinical findings
8.) Diagnosis
• TRAPS– Genetic testing
9.) Treatment of the Child with Periodic Fevers
• PFAPA– No cure – 1-2 mg/kg prednisone give over 1-2 doses x1 just
prior to the onset of a febrile episode may abort that episode (85% or so of cases)
– The next episode may occur sooner than expected half the time in 50% of patients
– This may be diagnostically useful
Wurster, et al. J Pediatr. 2011;159:958-964Padeh, et al. J Pediatr. 1999;135:98-101
9.) Treatment of the Child with Periodic Fevers
• PFAPA– Would not use ‘around the clock’ prednisone to
prevent PFAPA episodes given side effects of prednisone
– Would not use monthly prophylactic prednisone given propensity to increase the frequency of episodes (may turn a once monthly illness into a weekly affair, with the need for more and more steroids)
9.) Treatment of the Child with Periodic Fevers
• PFAPA– Could consider selective use of such prednisone to
abort febrile episodes prior to important events a few times per year (e.g. wedding, vacation) should an episode began during or prior to the event
2.) The Major Playersa.) PFAPA Syndrome
• PFAPA– Continuous cimetidine has been studied– 8/28 patients with PFAPA responded to 6-12
months of treatment with resolution of fevers in 1 study and 7/26 in another
– Fevers may recur when cimetidine is stopped
Thomas, et al. J Pediatr. 1999;135:15-21Feder, et al. Acta Paediatr. 2010;99:178-184
9.) Treatment of the Child with Periodic Fevers
• PFAPA– Tonsillectomy/adenoidectomy– Variable literature• 15 studies (11 retrospective) and 149 children• Only 2 RCT’s with 33 patients• Variability in surgery performed (tonsillectomy or
tonsillectomy/adenoidectomy)• Variability in diagnosis of PFAPA• Variability in follow-up
Garavello, et al. J Pediatr. 2011;159:138-142
9.) Treatment of the Child with Periodic Fevers
• PFAPA– However, the data (such as it is) tends to be
favorable– Very invasive treatment for a self-limited disease
9.) Treatment of the Child with Periodic Fevers
• Cyclic Neutropenia– GCSF may shorten the period of neutropenia
Horwitz, et al. Blood. 2007;109:1817-1824
2.) The Major Playersb.) Hyper IgD Syndrome
• No established treatment• Studies suggest some benefit to predisone,
anikinra and etanercept
Van der Hilst, et al. Medicine. 2008;87(6):301-10
9.) Treatment of the Child with Periodic Fevers
• Familial Mediterranean Fever– Colchicine• Reduces severity or eliminates attacks in 85-90% of
patients
Drenth, et al. NEJM. 2001;345(24):1748-57
9.) Treatment of the Child with Periodic Fevers
• TRAPS– Etanercept– High dose prednisone