The Child With Recurrent Fever

The Child with Recurrent Fever:
The Alphabet soup of Periodic Fever
Syndromes
Suzanne C Li, MD PhD
Joseph M Sanzari Children’s Hospital
Division of Pediatric Rheumatology
1
Overview
• Fever
• Recurrent fever
• Periodic Fever Syndromes
• Features of Periodic Fever Syndromes
• Evaluation of a child with recurrent fever
• Innate immunity
• Autoinflammatory Diseases
2
Fever
• Very common symptom in children
• Usually short-lived, benign
• Prolonged fever without obvious cause
fever
of unknown origin (FUO)
• duration: minimum 14-21 days
• Recurrent fever: Different patterns
• Single illness with waxing and waning course
• Repeated unrelated illnesses of same organ system
• Multiple illnesses of different organ systems
• Periodic fevers: recurring episodes with similar sx
3
Marshall G, J Infection 2014;68(suppl):S83 Long, S. Ped Clin N AM 2005;52:811
Recurrent Fever: could represent
• Recurrent infections
•Viral: common for 2-3 yo to have 6-10 URI/yr
•daycare, school aged sibs
•Bacterial: may be 2o to
•structural anomaly, cystic fibrosis, immunodeficiency
•Parasite: travel history
• Malignancy: lymphoma, leukemia
• Systemic inflammatory d: rheum, IBD
•Systemic Juvenile Arthritis, Lupus, Behcet’s, Vasculitis
•Periodic Fever Syndromes
4
Marshall G, J Infection 2014;68(suppl):S83 Long, S. Ped Clin N AM 2005;52:811
Periodic Fever Syndromes (PFS)
• Recurrent, self-limited febrile episodes
• Fever is a major feature
• Other sx are similar, predictable
• Episodes last days to few weeks
• Clockwork or irregular periodicity
• Well in between episodes
• Normal labs in between episodes
•Different than systemic inflammatory d, malignancy
• Normal growth and development
5
Periodic Fever Syndromes
• Cyclic neutropenia: fever 2o to infection
• Classical PFS: Not associated with infection
•Hereditary
•FMF = Familial Mediterranean Fever
•HIDS = Hyper-immunoglobulin D Syndrome
•TRAPS = Tumor-Necrosis-Factor ReceptorAssociated Periodic Syndrome
•FCAS = Familial Cold Autoinflammatory Syndrome
•Non-hereditary PFS
•PFAPA = Periodic fever, aphthous stomatitis,
pharyngitis, adenitis
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Periodicity of PFS
• Very Regular, Predictable
• Cyclic neutropenia
• PFAPA
• Variable regularity
•Familial Mediterranean Fever
•Hyper-immunoglobulin D Syndrome
• Least regular
•Tumor-Necrosis-Factor Receptor-Associated Periodic
Syndrome
•Familial Cold Autoinflammatory Syndrome
Drenth and van der Meer, 2001
7
Cyclic Neutropenia
• Presents within first few months of life
• Most regular fever episodes: every 21 days
• Neutropenia (<200 cells/mm3) lasts 3-5 days
• Develop infection during nadir
• Dx: serial CBCs: WBC often normal at time of fever
8
Dale and Hammond, 1988
Cyclic Neutropenia
•Common sx and problems:
•Apthous stomatitis, pharyngitis, gingivitis, periodontitis,
OM, sinusitis, lymphadenopathy
• cellulitis, furunculosis
• Fatigue, headache, myalgia, abdominal and bone pain
•Defect: ELA2: neutrophil elastase gene
•About 1/3 familial: Autosomal Dominant
•ELA2 defects also  severe congenital neutropenia
• Rx: G-CSF
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Classical Periodic Fever Syndromes:
Clinical and Laboratory pattern
• Acute onset of fever: T103-105oF
• may have prodrome few hours to 1 day before
• High inflammation during febrile episode
• ESR, CRP ; CRP can be >100
•  WBC in some
• If prolonged episode (i.e.,TRAPS), anemia,
thrombocytosis may be present
• End of episode: rapid improvement in sx
• Complete normalization of labs for most
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Hausmann & Dedeoglu, Dermatol Clincs 2013;31:484 Hofer et al Rheumatol 2014
PFAPA (Periodic fever, aphthous
stomatitis, pharyngitis, adenitis)
• Most common Periodic Fever Syndrome
• Median age of onset: 1.7-2.7 yr (range 0.1-12 yr)
• Episodes:
•Duration 4 d (range 1-10 d)
•Interval between episodes 4 wk (range 1-12)
• Features:
• Aphthous Stomatitis: 21-70%
• Pharyngitis: 61-90%
• Cervical Adenopathy: 46-88%
drpaulose.com
11
Hausmann & Dedeoglu, Dermatol Clincs 2013;31:484 Hofer et al Rheumatol 2014
PFAPA Diagnotic Criteria
1.Regularly recurring fevers beginning by age 5yr*
2.Constitutional sx in absence of URI with at least 1
of following:
apthous stomatitis, cervical lymphadenitis, pharyngitis
3.Rule out cyclic neutropenia
4.Asymptomatic in between episodes
5.Normal growth and development
*adolescent and adult onset has been reported
Feder et al J Pediatr 1999;135:15
12
PFAPA Symptoms and Course
• Prodrome: fatigue, HA, irritability, abdominal pain
• Other sx: nausea, diarrhea, lethargy, myalgia
•Arthralgia but NOT arthritis
•No genetic basis identified, all ethnicities
• 12% Family Hx of PFAPA
• M > F 1.2-2.3 to 1
•Prognosis excellent
•Mean disease duration 6.3 yr (range 5.4-7.3)
•15% have persistent d but  severity
•No long-term sequelae
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PFAPA Treatment
• Treatment related to discomfort of child, family
• No identified long-term problems
• Disease self-limited in most patients
• Supportive: anti-pyretics
• Abort episodes:
•Corticosteroid: 84-90+% respond to 1-2 doses
•But may  episode intervals
•Anti-IL-1, anti-TNF reported to be effective
• Prevent episodes:
• Cimetidine: 27-40%
• Tonsillectomy: 64-100%
Hausmann & Dedeoglu, Dermatol Clincs 2013;31:484 Wurster et al J Pediatr 2011;159:958
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Familial Mediterranean Fever (FMF)
• Most common inherited PFS: Aut Recessive
•  Sephardic Jews, Armenians, Arabs, and Turks
• Genetic defect: MEVK gene = pyrin
Hypothesized founder migration
Zadeh et al Genetics Med 2011;13:263
Hashkes and Toker, Ped Clin N Am 2012;59:447
15
Hausmann & Dedeoglu, Dermatol Clincs 2013;31:484
Familial Mediterranean Fever (FMF)
• 80% present by age 10 yr
• Mean onset age 9.6 yr; 30% < 2 yo
• Episodes:
• Duration: 12-72 hr
• Intervals: monthly to irregular intervals (1/wk to 1/yr)
• Most common Features:
•Serositis: peritonitis > pleuritis > pericarditis
• Arthritis: usually knee or ankle
• Rash: Erysipelas on extremities
• Pattern can change; varies with residence
•may initially only have fever
Hashkes et al, Ped Clin N Am 2012;59:447
16
Hausmann et al, Derm Clincs 2013;31:484 Drenth and van der Meer, NEJM 2001
FMF Symptoms
• Abdominal pain: 95%
• can mimic acute appendicitis
• diarrhea, nausea, vomiting, and constipation
• Arthritis: 37-77%
Y. Kimura
•Monoarticular > poly, migratory, spondylo
• Chronic 5-10%
• Pleuritic pain: 23-62%
• Rash: 7-34%
• Splenomegaly, but not LA
• Less common: myalgia: exercise induced, HA,
vasculitis (HSP, PAN, GN), orchitis, scrotal swelling
Tripathi Dermatol Clinic
2013;31:387
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FMF Dx: Tel-Hashomer Criteria
• Major Criteria:
•Typical attacks (recurrent (>3 of same type), short (12-72h), febrile)
•Peritonitis (generalized)
•Pleuritis or pericarditis
•Monoarthritis of hip, knee, or ankle
•Fever alone
• Minor Criteria
•Incomplete attacks involving 1 or more of following sites
•Chest
•Joint
•Exertional leg pain
•Favorable response to colchicine
Definite: >1 major or >2 minor
Livneh et al Arthritis Rheum 1997;40:1879
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FMF Problems and Treatment
• Major complication: amyloidosis
• Can be fatal
• Risk related to geographic residence, FHx, Male,
specific genetic mutations
• Difficult to detect; proteinuria, US doesn’t have blood
assay
• Colchicine 1-2 mg/d prevents attacks in 60-70% of pt
•  number of attacks in 20-30%
•  amyloidosis risk in 95%
• anti- IL-1 agents can help if colchicine resistant
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Hyper-immunoglobulin D
Syndrome (HIDS)
• Also known as Mevalonate Kinase deficiency
• Mean age of onset 6 mo
• FHx, Autosomal recessive, Dutch, W. Europe
• Genetic defect: MVK gene: mevalonate kinase
• Episodes: High, sustained fever
• Duration: 3-7 d
• Interval: 3-8 wk
• Triggered by vaccination,
surgery, stress
Hashkes et al, Ped Clin N Am 2012;59:447
20
Drenth and van der Meer, NEJM 2001
HIDS Symptoms
• Prodrome:
• Headache, Fatigue, Congestion, Dry throat, Vertigo
• Abdominal pain
• Vomiting, Diarrhea
• Rash: polymorphous
• Cervical LA
• Apthous ulcers: ~50%, genital too
• Arthralgia/Arthritis of large joints
• Labs: often IgD, IgA, urine mevalonic acid
Drenth and van der Meer, 2001; Kastner
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HIDS Treatment
• NSAIDs: sometimes helpful
• Corticosteroids: can reduce fever duration
• anti-TNF agent: 65% responded
• anti-IL-1 agent: 89% responded
• Long term prognosis is good
•Rarely amyloidosis, glomerulonephritis
ter Haar et al ARD 2013;72:678
22
Tumor-Necrosis-Factor ReceptorAssociated Periodic Synd. (TRAPS)
• Median onset 3 years, range 2 weeks - 53 years
• FHx: autosomal dominant
• Genetic defect: TNFRSF1A gene: TNF receptor
• Ethnicity: many, initially identified in Irish
• Episodes: Prolonged fever
• Duration: 3 weeks, up to 6 wk
• Interval: 5-6 wk to months
•2-6 episodes/yr
• Can be triggered by exercise
23
Drenth and van der Meer, NEJM 2001
TRAPS Symptoms
• Myalgias: migrates peripherally
• Associated with stiffness
• Rash: red, tender, warm
•Overlies and migrates with myalgia
• Serositis: peritonitis, pleuritis
Toro, et al, Arch Derm 2000
• Conjunctivitis, periorbital edema, uveitis, iritis
• Arthralgia: large joints
• Occ. pharyngitis, apthous stomatitis
•Testicular pain
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Kastner
TRAPS Problems and Treatment
• NSAIDs for mild episodes
• Corticosteroids for severe episodes
•Can lose efficacy over time
• Colchicine helpful for some
• anti-TNF helpful for some
•May lose efficacy over time
• anti-IL-1: can help some that fail other rx
• Risk of amyloidosis 14-25%
Hashkes et al, Ped Clin N Am 2012;59:447
ter Haar et al ARD 2013;72:678
25
Familial Cold Autoinflammatory
Syndrome (FCAS)
• Onset within first 6 months in 95%
• FHx: Autosomal Dominant
• Gene defect: CIAS1 = cryopyrin
• Episode: triggered by cold exposure
Kastner D
• Mean time between cold exposure & episode: 2.5 hr
• Duration: average 12 hr; < 24 hr
• Symptoms: Fever 93%
• Urticaria: 100%
• Arthralgia: 96%
• Conjunctivitis: 84%
Hoffman H et al. J All Clin Immunol 2001;108;615
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FCAS, MWS, NOMID: Cryopyrinassociated Periodic Syndromes (CAPS)
• Defects in same gene associated with 3 different diseases
• Muckle Wells Syndrome (MWS): Episodes last up to 7 d
• ~ FCAS: fever, urticaria, arthralgia, conjunctivitis
• Sensorineural hearing loss, uveitis, HA, abd pain
• 25% amyloidosis
• Neonatal-onset Multisystem Inflammatory D. (NOMID, aka
CINCA): can present at birth
• Chronic, continuous inflammation
• All of MWS sx plus Aseptic meningitis, Blindness, Mental
retardation, Arthropathy, Dysmrophic faces
• 20% amyloidosis
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Treatment of CAPS
NOMID
• NSAIDS, Corticosteroids
• Symptomatic relief for ~2/3
• Does not induce remission
• Anti-IL-1 agents
• Complete remission in 64-79%
• Partial response in 25-34%
• May not be able to control aseptic meningitis
or bone dysplasia
Nomidalliance.org
28 D
Kastner
Work-up for recurrent fever
• Fever and symptom diary
•Length of illness, frequency, sx, temperature
• Evaluate patient during and between episodes
• History:
•Family hx, exposure, travel, drugs
• Labs during and between episodes
•Expect to see inflammation that resolves
•Need frequent serial CBCs to detect cyclic neutropenia
• Remember, PFS are rare!
•Consider other dx first!
Marshall 2014 J. Infection
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Diagnosis of Hereditary PFS
• Diagnosis should be based upon clinical
features, history, laboratory studies
•Genetic analysis expensive, should not use as
screening tool
• Discrepancies between identified and expected
genetic analysis
•FMF: ~30% have only 1 mutant MEFV allele
•~60% of pt with autoinflammatory phenotype pattern
do not have mutation in any of known gene loci
Kastner et al Cell 2010;140:784
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Hereditary PFS have led to major
advances in understanding immunity
• Two types of immunity:
•Acquired: T and B lymphocytes
•Unique receptors generated through recombination,
somatic mutation after antigen activation
•Innate: non-modifiable immune protection
•PFS have defects in innate immune system
•CAPS, FMF, HIDS: inflammasome or its function
•TRAPS: mutant receptor affects effector cell survival
• PFS defects   inflammation
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Innate Immunity
Universal Pathogen protection mechanism
• Found in plants, invertebrates, vertebrates
• Effector cells recognize microbial molecules,
cellular waste
• Macrophage, Dendritic cell, Monocytes, Neutrophils
• Recognize pathogens thru Pathogen Recognition
Receptors (PRRs)
• Binding to PRR  Inflammatory response
• Secretion of cytokines and chemokines
• Recruitment of immune cells
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Pathogen recognition leads to
inflammation
Recognition of pathogens by effector cell
receptors (TLRs and other PRRs)
Binding to PRR triggers
•  cytokine synthesis
•Inflammasome activation
•  cleavage of pro-IL-1
 active IL-1
CAPS, FMF, HIDS: defects
related to inflammasome
IL-1 causes:
• Fever
• Recruitment of leukocytes
• Activation of lymphocytes
33
Hashkes and Toker, Ped Clin N Am 2012;59:447; Hofmann 2011; Zen 2013
Hereditary PFS = Monogenic
Autoinflammatory Diseases
• New name based upon pathology
•Autoinflammatory diseases
•In contrast to Autoimmune diseases
•Autoantibodies and reactive T cells not found in
autoinflammatory diseases
• Il-1 plays key role in Autoinflammatory diseases
• Autoinflammatory processes now recognized as
involved in many other diseases
34
Diseases with an Autoinflammatory
Component
• Systemic Juvenile Idiopathic Arthritis,
Spondyloarthritis
• Crohn’s disease
• Gout
• Type II Diabetes
• Atherosclerosis
• Contact Dermatitis
• Vitiligo
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Thank You
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