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Periodic Fevers in Children

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

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Periodic Fevers in Children

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

  2. 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

  3. 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

  4. 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

  5. 2.) The Major Playersa.) PFAPA SyndromeReview 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

  6. Presentation of PFAPA: 6 Case Series, 395 Patients

  7. 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

  8. 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

  9. 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

  10. 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;24:1748-57 Van der Hilst, et al. Medicine. 2008;87(6):301-10

  11. 2.) The Major Playersb.) Hyper IgD Syndrome • Autosomal recessive • Affected siblings may be present Drenth, et al. NEJM. 2001;345(24):1748-57

  12. 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;46:1597-1600 Va der Hilst, et al. Medicine. 2008;87(6):301-10 Drenth, et al. NEJM. 2001;345(24):1748-57

  13. 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

  14. 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

  15. 2.) The Major Playersc.) Familial Mediterranean Fever • Erysipelas like lesions on shins/feet in 7-40%

  16. 2.) The Major Playersd.) TRAP Syndrome • TNF-Receptor Associated Periodic Syndrome • Also referred to as Familial Hibernian Fever

  17. 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

  18. 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

  19. 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

  20. 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?

  21. 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

  22. 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

  23. 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

  24. 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?

  25. 3.) Key Historical Features: Questions to Ask • Is the child otherwise well when not having a febrile episode?

  26. 4.) Key Physical Examination Features • Verification of fever • Oral ulcers • Lymphadenopathy • Rashes • Conjunctivitis • Arthritis • Pharyngitis

  27. 5.) Key Laboratory Features • Are inflammatory markers elevated (e.g. CRP, ESR, WBC, platelets) during febrile episodes? • Do inflammatory markers normalize when afebrile?

  28. 6.) Other Periodic Fever Syndromes • Neonatal onset multi-system inflammatory disease • Muckle-Wells syndrome • Familial cold-urticaria • Majeed syndrome

  29. 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

  30. Frequency/Periodicity of Various Periodic Fever Syndromes

  31. 7.) Practical Approach to the Child with Periodic Fevers • 3rd---Determine the length of episodes

  32. Duration of Febrile Episodes in Various Periodic Fever Syndromes

  33. 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)

  34. 7.) Practical Approach to the Child with Periodic Fevers • 5th---Assess via history and examination for syndrome specific physical examination findings

  35. Examination Findings Associated with Various Periodic Fever Syndromes

  36. 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)

  37. 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)

  38. 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? Evaluate for more serious etiology (e.g. Rheumatologic, Oncologic) No Yes Age onset <1 year? Findings Fit? Neutropenia q 3 weeks, Fevers q 21 days, oral ulcers, Recurrent bacterial infections Cyclic Neutropenia No Yes Assess Frequency of Fever Hyper IgD Syndrome Abdominal pain, rash, diarrhea, splenomegaly Regular Irregular Findings Fit? Findings Fit? Abdominal pain, rash, diarrhea, splenomegaly Neutropenia q 3 weeks, fevers q 21 days, oral ulcers, recurrent bacterial infections q 21 days q 4-8 weeks Cyclic Neutropenia Hyper IgD Syndrome q 3-6 weeks Pharyngitis, cervical adenitis, oral ulcers Weeks to months Abdominal pain, rash, arthritis PFAPA FMF Abdominal pain, rash, diarrhea splenomegaly Abdominal pain, rash, periorbital edema, arthritis q 4-8 weeks Hyper IgD Syndrome Weeks to years TRAPS

  39. 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

  40. 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

  41. Hyper IgD Syndrome/PFAPA/Cyclic Neutropenia---Differentiating Features

  42. 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

  43. 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

  44. 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

  45. 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)

  46. 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

  47. 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

  48. 8.) Diagnosis • Hyper IgD Syndrome • Genetic testing • IgD and IgA levels

  49. 8.) Diagnosis • Familial Mediterranean Fever • Genetic testing • Clinical findings

  50. 8.) Diagnosis • TRAPS • Genetic testing

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