Periodic Fevers in Children Walter Dehority, M.D., MSc

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