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

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Presentation on theme: "Periodic Fevers in Children Walter Dehority, M.D., MSc."— Presentation transcript:

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 Players a.) 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;110:43-46 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 SymptomMarshall, et al Thomas, et al Padeh, et alTasher, et al Gattorno, et al Feder, et al Mean duration fever (days) ---4.8 5.34.54.1 Pharyngitis %7565100968485 Cervical LAD % 6777100618462 Apthous stomatitis % 756768395938 Headache %---6518464144 Arthralgia %--- 11---44--- Diarrhea %---300001329--- Abdominal Pain % ---4518655341 Rash %---15---422---

7 2.) The Major Players a.) 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 Players a.) 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 Players a.) 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 Players b.) 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 Players b.) Hyper IgD Syndrome Autosomal recessive – Affected siblings may be present Drenth, et al. NEJM. 2001;345(24):1748-57

12 2.) The Major Players b.) 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 Players b.) 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 Players c.) 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 Players c.) Familial Mediterranean Fever Erysipelas like lesions on shins/feet in 7-40%

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

17 2.) The Major Players d.) 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 Players e.) 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 Players e.) 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 Players f.) 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? 2 nd ---determine the frequency/periodicity of the episodes

30 Frequency/Periodicity of Various Periodic Fever Syndromes Frequency of Episodes PFAPA Cyclic Neutropenia FMFHIDSTRAPS Rangeq 3-6 weeksq 2-8 weeksq 3-4 months q 4-8 weeksq weeks to years ‘Classic’q 28 daysq 21 days (90%) None

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

32 Duration of Febrile Episodes in Various Periodic Fever Syndromes PFAPA Cyclic Neutropenia FMFHIDSTRAPS 3-5 days5-7 days1-3 days3-7 days2 days-weeks

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 FindingPFAPA Cyclic Neutropenia FMFHIDSTRAPS Oral UlcersYes NoYesNo PharyngitisYesNo Cervical LADYesNo YesNo RashNo Yes SplenomegalyNo YesNo Periorbital edema No Yes PseudocellulitisNo Yes

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? 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? RegularIrregular q 21 days q 3-6 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 infections Pharyngitis, cervical adenitis, oral ulcers Abdominal pain, rash, diarrhea splenomegaly Abdominal pain, rash, diarrhea, splenomegaly Abdominal pain, rash, arthritis Abdominal pain, rash, periorbital edema, arthritis Hyper IgD Syndrome FMF TRAPS No Yes

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 VariablePFAPACyclic NeutropeniaHyper IgD Syndrome Age at onset2 years<1 year in 90%<1 year often RashNo Often Recurrent Bacterial Infections NoYesNo Abdominal Pain/Diarrhea OccasionallyNoFrequent Periodicity3-6 weeks, normally 4 weeks 21 days >90% of time 4-8 weeks

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

51 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;159:958-964 Padeh, et al. J Pediatr. 1999;135:98-101

52 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)

53 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

54 2.) The Major Players a.) 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;135:15-21 Feder, et al. Acta Paediatr. 2010;99:178-184

55 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

56 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

57 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

58 2.) The Major Players b.) 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

59 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

60 9.) Treatment of the Child with Periodic Fevers TRAPS – Etanercept – High dose prednisone


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