APPROACH TO PERIODIC FEVER SYNDROMES

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APPROACH TO PERIODIC FEVER SYNDROMES

• Sarah S. Long, M.D.
• Professor of Pediatrics
• Drexel University College of Medicine
• Chief, Section of Infectious Diseases
• St. Christophers Hospital for Children
• Dr. Long has no conflict to disclose

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Case

• A 15-year-old girl is referred because of a
• persistent febrile illness. Twelve weeks ago
• she had the acute onset of fever to 1030,
• headache, myalgia, sore throat and nasal
• congestion. A throat culture was negative
• for group A streptococcus. Over the next
• week high fever and congestion abated but
• parents report that she has had persisting low
• grade fever (to 99.8 every 2-3 days),
• complains of headache, sore throat,
• weakness, fatigue, and has poor color, poor
• appetite. She complains of sudden shooting
• pains in arms and legs.

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Case continued

• On attempt to return to school 4 weeks
• ago she was there only 2 hours when the
• school nurse reported that the patient
• felt faint, chilly and sweaty, and was
• unable to stay in class. She has not
• returned to school and is now home
• tutored.
• What is your next diagnostic step?

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APPROACH TO DX PERSISTING SYMPTOMS I
Past Hx
No significant medical A student Swim
team Church choir Local volunteer
Current Hx
Temps
Peaks 4-8 PM, lt1000
Relieved acetaminophen Does not awaken No vomiting
Headache
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APPROACH TO DX PERSISTING SYMPTOMS II
Current Hx
Sore throat
Prominent AM only Not worse swallowing
Weakness
Not prox/distal/truncal
Fatigue
Asleep lt 10 hrs night Not asleep during day
Poor color
Pale, not cyanotic
Poor appetite
Weight gain/no loss
Shooting pains
Multiple areas, durations lt10 sec
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APPROACH TO DX PERSISTING SYMPTOMS III
Resp. congestion Eyes weird Skin fleeting
rashes Heart jumps Not hungry Stomach
weird Feels faint
ROS
Family Hx
Mother fibromyalgia, ib Grandmother
hospice Father night work Schedules _at_ patient
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APPROACH TO DX PERSISTING SYMPTOMS IV
PE
80ile Ht, 90ile Wt, HR 110, BP 100/62 Animated,
flushed, helpful Normal general exam Normal
musculoskeletal neuro Normal eye grounds
Lab
Hb 12.8, WBC 10,200 (60P), Pl 238K Chem screen
WNL ESR 9 UA WNL
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• Whats the differential diagnosis?
• What further evaluation should be done?

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APPROACH TO DX PERSISTING SYMPTOMS V
Signs_____
Summary Symptoms__
Fevers Headache Sore throat Weakness Fatigue Poor
color Poor appetite Shooting pains
Congest Eyes Rashes Heart Appetite Stomach Faint C
hilly
Normal weight Normal vital signs Normal
exam Normal simple labs
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DIFFERENTIAL DIAGNOSIS
Prior to vs After Interview
Prior to vs After Exam
Prior to vs After Lab Tests
After all
Abused
Depressed
Fatigued
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DEMO PSYCHO SYMPTOMS BY ILLNESS

• Fatigued Depressed JIA
• White race
• Femalegtgtmale
• Low socioeco
• High parent ed
• Acute onset
• Overachiever

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PSYCHOLOGICAL SYMPTOMS BY ILLNESS

• Fatigued Depressed JIA
• Social/extra act
• Sad all the time
• Lonely
• Hate/want to hurt self
• Not as good as others
• Dont get along/not liked
• Feel overtired
• Not much energy
• Somatic complaints
• See doctors alot
• Need help
• Internalize stress
• Carter BD. Dev Beh Ped 1996 Carter BD.
  Pediatr 1999

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TIMELINE EVIDENCE BASE FATIGUE
1990s
NIH definition CFS
Case series pediatrics
Immunologic studies
EBV, other ID
2000s
Lyme, other ID
Follow-up case series
Non Dx pediatrics
Endocrine hypoadrenia
Cardio neurally med. hypotension
postural tachy syndrome
Joint hypermobility ?Ehlers Danlos
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EVIDENCE BASE FATIGUE
Orthostatic instability in a population-based stud
y of chronic fatigue syndrome. Jones JF et al.
Am J Med, December 2005 58 adults CFS 55
controls Inpatient 2-day evaluation
Head-up tilt test pos. 30 CFS vs 48
controls
Endurance exercise training in orthostatic intoler
ance a randomized controlled trial. Winker R et
al. Hypertension Mar 2005 Military recruits
36 orthostatic intol Randomized to
training vs control x 3mo Outcome OI
6/11 training vs 10/11 control Symptom
scores sig in trained
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TYPICAL FINDINGS IN PATIENTS WITH
DECONDITIONING

• Age gt 12 years
• Preillness achievement high
• Family expectations high
• Acute febrile illness with onset easily dated
• Family and outside attention high
• Lengthy list, but vague complaints
• Odd complaints (eg, shooting pains 30-
• second blindness stereotypic sporadic,
• brief unilateral tremors, jerks, or
  paralysis)
• No daytime sleep
• Preserved weight
• Extreme cooperation with examination
• Normal physical and neurologic examination
• Normal results of screening laboratory tests

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MANAGEMENT DECONDITIONING
Patient Validate symptoms as accurate
Incremental, forced return to school
Exercise Predict symptoms No
school absence w/o ped. visit No
expectation performance
Family Validate their concern Validate
their medical pursuit Justify your
diagnosis Change focus to health
Avoid How do you feel? No expectation
performance
10 Provider Quarterback
Long approach gt1975
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CASE

• 4 yr old adopted boy of mixed races
• Age 1 yr Febrile illnesses q 30 days
• Age 2 yr Characteristic fevers q 30 days
• Temp 1020 1030 x 3 days
• Swollen cervical nodes
• Age 3 yrs Same char periodicity
• ROS No rash, URI, H/A, arthritis
• No mouth ulcers
• Completely well between episodes
• Good growth/development
• Immunizations fever

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• Exam Healthy, no dysmorphic, activity
• Height weight 75ile
• Normal tonsils, nodes, skin, joints
• Normal abdomen
• Tests Hb 10.2 11.8
• WBC lt 10,000 (healthy)
• 10,000 15,000 (episodes)
• Neutrophils normal or , mild shift
• Platelets not elevated
• ESR 20 (healthy), 50-70 (episode)
• Normal immunoglobs (IgD2 mg/dL)
• Chem, HIV, Sickle, Hb electro

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APPROACHING RECURRING FEVER ILLNESSES
History History History
Prolonged or relapsed single illness Multiple
simple illnesses Recurrences at irregular
intervals
Recurrences regular/predictable/clockwork Duration
Response to antipyretics, NSAIDs,
antibiotics Occurrence with immunizations
Additional Features of Episodes
Symptoms URI, AOM
Target organ? Rash? Mouth ulcers?
Cardinal feature
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MORE HISTORY
Interval between episodes
Lingering symptoms Multiple URIs, asthma Severe
bacterial/viral infections
Perfectly well, energetic Few regular
illnesses Good growth development
Family History
Genetic background Sibs not ill with
patient Autoimmune, -inflammatory dis Amyloidosis
Parent w fevers as child
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PHYSICAL EXAMINATION
Growth chart Thorough general Target organ Mouth
ulcers, rashes, joints, nodes
TESTS
Simple - during episode interval CBC, Chem,
ESR Immunoglobulins Urine culture
Imaging only as directed by exam
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PFAPA SYNDROME

• PF Periodic Fever 100
• A Aphthous stomatitis 70
• P Pharyngitis 72
• A Adenopathy 88

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CHARACTERISTICS OF PFAPA
Addl SCHC Clockwork cycles Pro 2h
glassy Fever is cardinal Well between
Happy parents Happy child Fewer colds
Parent hx fevers
Vanderbilt Male Female 1.2 Onset
PFAPA 2.8y Max temp 40.50 Duration
fever 3.8d Duration epi 4.8d
Episodes/yr 11.5 Well interval 28.2d
Mean WBC 13,000 Mean ESR 41
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FOLLOW-UP PFAPA

• Natural History
• Mean follow-up 3.3y (1m 9.4y)
• Mean age F/U 8.9y
• Char. episodes As at diagnosis
• Resolution 41
• Mean duration 4.5y
• Treatments
• Cimetidine Rx and prophylaxis
• Prednisone Aborts epi but freq
• Tonsillectomy Resolution in 64
• Thomas KT etal J Pediatr 199913515-21

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HISTORY OF PFAPA

• 1987 Syndrome described (TN)
• 1992 Cimetidine Rx (CT)
• 1989 Tonsillectomy Rx (NC)
• 1990s Cases gt 100 TN
• Cases gt 100 PA
• Cases Israel, Spain, France,
• Italy, Greece

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Resolution of PFAPApost tonsillectomy
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WHAT IT ISNTWHAT IS IT?

• K I N E C T I O N

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MANAGEMENT PFAPA
Diagnosis
Clinical best (Tests IgAD, WBCs)
Re-visit
Beware extra SS
Must be well between
Management (Sequential)
Support
Cimetidine
Pred dx trial
Pred special circ
Tonsillectomy
GET HELP IF OFF EXPECTED
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CYCLIC NEUTROPENIA

• Onset lt 5 yrs Common
• Often lt 1 yr
• Length fever epi 5-7 days
• Interval between 3 weeks
• Assoc. symptoms Ulcers Gingivitis
• Rare clostridia
• Growth dev
• Ethnic/geographic None
• Auto dominant
• Lab findings Neutropenia
• Etio/Diagnosis Neutrophil elastase
• Apoptosis myeloid
• Twice wkly WBC
• Treatment G-CSF

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• Autoinflammatory syndromes
• Seemingly unprovoked inflammation
• without significant autoantibodies
• and autoreactive T lymphocytes
• McDermott

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PERIODIC FEVER SYNDROMES

• Periodicity Other Sympt Inher
  Etio_______
• PFAPA Yes No No No
• Cyc Neutro Yes Gingivitis AD
  ELA2
• AOM, Sinus Apop marrow
• FMF No Polyserositis AR MEFV
• Rashscrotal Pyrin
• HIDS Yes/No Abdom pain AR MVK
• Rashes MVKase
• Mood swings
  Isoprenoids
• Immun trigger
• TRAPS No Myalgia AD TNFRSF1A
• Pseudo cell TNF receptor
• Periorb edema

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HYPER IMMUNOGLOBULIN D (HIDS)

• Onset lt 5 yrs Common
• Length fever epi 4 days
• Interval between 4-8 wks, non-periodic/P
• Assoc. symptoms Abdom pain/diarrhea
• Arthralgia
• Rashes, splenomegaly
• Immun. trigger
• Ethnic/geographic Dutch, French, others
• Auto recessive
• Lab findings IgD, IgA
• Etio/Diagnosis Mutations MVK
• Mevalonic kinase
• Urinary mevalonate
• Treatment ? Etanercept
• ? Simvastatin

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TNFR ASSOC. PERIODIC FEVER (TRAPS)

• Onset lt 5 yrs Uncommon
• Length fever Days to weeks
• Interval between Not periodic
• Assoc. symptoms Pseudo cellulitis rash
• Arthritis
• Ethnic/geographic Irish, Scot
• Others (FMF)
• Auto dominant
• Lab findings Serum TNFR1
• Etio/Diagnosis Mutation TNFRSF1A
• Treatment Corticosteroid
• Etanercept

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Case

• Onset lt 5 yrs Yes
• Length fever epi 3 days
• Interval between 4 wks, well
• Assoc. symptom Mood change
• Abdominal pain/V
• Immunization trigger
• Ethnic Mixed racial
• Lab findings Acute phase react
• Treatment Cimetidine no effect
• Tonsillectomy no effect
• Age 7 years IgD 5 mg/dL, IgA 72 mg/dL

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• Missense mutations MVK
• HIDS

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