Recurrent Fever in the Pediatric Patient

1. Recurrent Fever in the Pediatric Patient Ping-Wei Chen Emergency Medicine Resident Much thanks to: Drs. Bryan Young, Graham Thompson, Susan Kuhn,Chris Waterhouse, Paivi Miettunen, Ron Anderson

2. +++ Concerned Parent • 4 year old boy • 5 weeks of intermittent fevers (Tmax 389C) • last “a few days” • fatigue, malaise • Unsure if ever completely gone • ?red rash the first few days • Walk-in clinic x 2 • “viral illness” • “the flu” • Negative urine dip • PLC ER • Today is visit #2

3. PLC ER Visit #1 • CBC • Hgb 96 • WBC 9.7 • Plt 530 • Electrolytes, Creatinine, BUN = normal • Urine dip, R+M negative

4. PLC ER Visit #2 • “5 weeks intermittent fevers” • Tmax 389C • ✓ fatigue/malaise • Øvomiting, Ødiarrhea • Ørespiratory symptoms • Øgenitourinary symptoms • ✓red rash “first few days” • Øsick contacts • From Turkey 6 months ago • Preschool student • Previously healthy • Immunizations UTD On exam • 379C, 100/65, 102bpm, 100% RAO2 • HNT normal • CV normal • Resp – clear, equal BS • Abdo – soft, nontender • MSK – Ørash/joint pain

5. Objectives • Discuss definitions • Recurrent Fever/Periodic Fever • Fever of Unknown Origin (FUO) • Outline differential diagnoses • Regular VS Irregular fever intervals • Describe an approach • Expert opinion • ID, GI, Rheumatology, Oncology

6. Definitions

8. Working Definition • Recurrent/Periodic Fever • Repeating episodes of fever separated by periods of normal temperature that return at regular or irregular intervals • Fever of Unknown Origin • Fever of greater than 3 weeks duration and uncertain diagnosis after 1 week of intensive investigation

9. Recurrent Fever • John and Gilsdorf 2003 • “≥3 episodes of fever in a 6 month periodwith no defined medical illness to explain the fever and with an interval of at least 7 days in between febrile episodes”

10. Recurrent/Periodic Fever • Long 2005 • Recurrent Fever • “A single illness in which fever and other signs and symptoms wane and wax” • Periodic Fever • “Recurring episodes of illness for which fever is the cardinal feature…with intervening intervals of weeks to months of complete well-being. Episodes can have either clockwork or irregular periodicity”

11. Fever of Unknown Origin • Petersdorf and Beeson 1961 • “fever persisting more than 3 weeks in duration, with documented temperatures of 38.3oC on several occasions, and uncertain diagnosis after intensive study of at least 1 weeks duration”

12. “Throw me a frickin’ bone here”

14. Etiology • “Common disorders with uncommon presentations” • INFECTION • Inflammatory/Autoimmune • Undiagnosed (recurrent)/Neoplasms (FUO)

15. Etiology

16. Etiology Ciftci et al. 2003 Pasic et al. 2006 Etiology FUO (n=185) Infection 37.8% Autoimmune 12.9% Kawasaki Disease 6.4% Malignancy 6.4% Misc. 8.1% Undiagnosed 30% • Etiology FUO (n=102) • Infection 44.2% • Collagen Vascular 6.8% • Malignancy 11.7% • Misc. 24.5% • Undiagnosed 12.8%

17. Recurrent Fever Differential Diagnosis Fever Intervals Regular? Irregular?

18. Fevers at Regular Intervals • Fever occurring at regular intervals • PFAPA syndrome* • Cyclic neutropenia • Relapsing fever (Borrelia spp. other than burgdorferri) • Undiagnosed cause* • Fever occasionally at regular intervals • Familial Mediterranean Fever • Hyper-IgD syndrome • EBV infection John and Gilsdorf 2002

19. Fever at Regular Intervals • Periodic Fever, Aphthous Stomatitis, Pharyngitis, and Cervical Adenopathy (PFAPA) • high fever q21-28 days • Leukocytosis, ESR • well/investigations normal between episodes • Tx: prednisone, cimetidine • No long-term sequelae

20. Fever at Regular Intervals • Cyclic Neutropenia • Uncommon • May be clinically indistinguishable from PFAPA • Usually no bacterial infection during neutropenia • Diagnosis: • CBC X2-3/week for 6 weeks (ANC <500) and spontaneous recovery • Bone marrow • If symptomatic, G-CSF

21. Fever at Regular Intervals • Relapsing Fever • Spirochetes of Borrelia genus (not burgdorferi) • Fevers 1-6 days separated by 4-14 days • “crisis” (BP,HR) followed by profuse diaphoresis, falling temperature, and BP. • Mortality for untreated fever during crisis and its aftermath • Treatment: penicillin or tetracycline

22. Fevers at Irregular Intervals John and Gilsdorf 2002

23. An Approach • Careful history & physical exam • Establish pattern of fever (fever diary) • Constant VS Recurrent • Duration • Associated symptoms • Hematologic exam • Hepatosplenomegaly • Lymphadenopathy

24. When to refer? • Dr. Susan Kuhn (Pediatric Infectious Diseases) • ≥3 episodes of recurrent fever

25. What to order? • Infectious Disease • Order: • CBC • Urine dip/R+M/C+S • Blood culture • ESR/CRP • EBV serology (IgM/IgG) • Quantitative immunoglobulins • Maybe: • CXRay – resp symptoms • Stool C+S/O+P – diarrhea • Thin/Thick blood smear – travel to endemic area ≤1 year

26. What to Order? • Dr. Chris Waterhouse (Paediatric GI) • Add: • Hepatobiliary studies (ALT, GGT, ALP, lipase) • Iron studies (ferritin, iron) • Albumin (losses/decreased production) • Stool studies (C+S, O+P, C. diff)

27. What to order? • Dr. Paivi Miettunen (Pediatric Rheumatology) • If referring directly to Rheumatology Clinic • Order: • CBC • Creatinine, Urea • ESR/CRP on days 1, 5, 10 of fever • Ferritin • IgD • Urine R+M • Urine Mevalonic Acid

28. What to Order? • Dr. Ron Anderson (Pediatric Oncology) • Order: • CBC • CXRay • if lymphadenopathy, hepatomegaly, splenomegaly, abdominal mass

29. Prognosis • Generally excellent • If no diagnosis after investigations • Fevers resolve • Growth/Development unaffected • No further testing unless new signs/symptoms

30. Back to our Case • Referred to urgent paediatrics • Bloodwork/Urine investgations unremarkable • No diagnosis • Fevers resolved • Still being followed by paediatrics

31. Conclusions • Recurrent Fever ≠ Fever of Unknown Origin • Differential Diagnosis are not the same • Urgent Paediatrics/Outpatient Paediatrics • Workup guided by ID/GI suggestions