Periodic Fevers in Children
Walter Dehority, M.D., MSc.
Outline
• 1.) Introduction
• 2.) The Major Players
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3.)
4.)
5.)
6.)
7.)
8.)
9.)
A.) PFAPA
B.) Hyper IgD Syndrome
C.) Familial Mediterranean Fever Syndrome
D.) TRAP Syndrome
E.) Cyclic Neutropenia
F.) Recurrent Viral Illnesses
Other Periodic Fever Syndromes
Key Historical Questions
Key Physical Examination Features
Key Laboratory Features
Practical Approach to Diagnosing a Child with Periodic Fevers
Diagnosis
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 Players
a.) 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;110:43-46
Thomas, et al. J Pediatr. 1999;135:15-21
Padeh, et al. J Pediatr. 1999;135:98-101
Gattorno, et al. Pediatr. 1009;124:e721-28
Feder, et al. Acta Paediatr. 2010;99:178-184
Tasher, et al. Acta Paediatr. 2008;97:1090-1092
Presentation of PFAPA: 6 Case Series, 395 Patients
Symptom
Marshall,
et al
Thomas,
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 Players
a.) 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 Players
a.) 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 Players
a.) 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 Players
b.) 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;24:1748-57
Van der Hilst, et al. Medicine. 2008;87(6):301-10
2.) The Major Players
b.) Hyper IgD Syndrome
• Autosomal recessive
– Affected siblings may be present
Drenth, et al. NEJM. 2001;345(24):1748-57
2.) The Major Players
b.) 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;46:1597-1600
Va der Hilst, et al. Medicine. 2008;87(6):301-10
Drenth, et al. NEJM. 2001;345(24):1748-57
2.) The Major Players
b.) 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 Players
c.) 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 Players
c.) Familial Mediterranean Fever
• Erysipelas like lesions on shins/feet in 7-40%
2.) The Major Players
d.) TRAP Syndrome
• TNF-Receptor Associated Periodic Syndrome
• Also referred to as Familial Hibernian Fever
2.) The Major Players
d.) 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 Players
e.) 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 Players
e.) 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 Players
f.) 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?
No
Evaluate for more serious etiology
(e.g. Rheumatologic, Oncologic)
Yes
Age onset <1
year?
No
Findings Fit?
Cyclic Neutropenia
Yes
Assess
Frequency of
Fever
Regular
Hyper IgD Syndrome Abdominal pain, rash,
diarrhea, splenomegaly
Findings Fit?
q 21 days
Cyclic Neutropenia
q 3-6 weeks
PFAPA
q 4-8 weeks
Hyper IgD Syndrome
Neutropenia q 3 weeks,
Fevers q 21 days, oral ulcers,
Recurrent bacterial infections
Neutropenia q 3 weeks,
fevers q 21 days, oral ulcers,
recurrent bacterial infections
Pharyngitis, cervical adenitis, oral
ulcers
Abdominal pain, rash, diarrhea
splenomegaly
Irregular
q 4-8 weeks
Findings Fit?
Abdominal pain, rash, diarrhea,
Hyper IgD Syndrome splenomegaly
Weeks to months
FMF
Abdominal pain, rash, arthritis
Weeks to years
TRAPS
Abdominal pain, rash, periorbital
edema, arthritis
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 21 days >90% of
4 weeks
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;159:958-964
Padeh, 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 Players
a.) 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;135:15-21
Feder, 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 Players
b.) 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