Periodic Fever and Allied Syndromes

Recurring episodes of i l lness of which fever is the

cardinal symptom with other associated symptoms

similar and predictable. The duration of symptoms are

days to weeks with intervening intervals of weeks to

months of complete well being. Episodes have either

clock like or irregular periodicity.

Introduction

Features Periodic fever syndrome

Periodically of episodes Clock like periodically or irregularlyfrequent or occasional

Characteristic of episodes Abrupt onset and end; fever dominant; No respiratory tract symptoms.

Clustering of episodes Episodes in all season; contact are not ill before and after

Course of episodes Identical predictable course

Internal between episodes Completely wall

Catch up growth and energy Excellent

Common periodic fevers

• Periodic fever, aphthous stomatitis, pharyngitis or adenitis/ Marshall syndrome (PFAPA)

• Cyclic Neutropenia• Familial Mediterranean fever• Hyper IgD periodic fever syndrome or Mevalonate Kinase

Deficiency• Tumour necrosis factor receptor associated periodic

syndrome

Periodic fever aphthous stomatitis, pharyngitis or adenitis/ Marshall syndrome (PFAPA)PFAPA was first described by Marshall et al. in 1987. It is a non-hereditary condition occurring sporadically. Clinical features Age – Usually before 3 years, almost always before 5 years.

Gender – Boys affected more than girls.

Fever- Usually high, lasting for 3 to 5 days ,poor response to antipyretics.

39-60% have aphthous ulcer.

Most cases have pharyngitis, tonsillitis and cervical lymphadenopathy.

Less common features – Headache, malaise, vomiting, chills.

Pharyngitis and tonsillitis Aphthous stomatitis

Diagnostic criteria for PFAPA1. Regularly recurrent with an age of onset (<5 years age)2. Constitutional symptoms in the absence of upper

respiratory infection with at least one of the following clinical signs :(a) Aphthous stomatitis(b) Cervical lymphadenitis(c) Pharyngitis

3. Exclusion of cyclic neutropenia4. Completely asymptomatic interval between episodes5. Normal growth and development

InvestigationImportant to rule out other febrile illness. Findings in Periodic Fever, Aphthous stomatitis, Pharyngitis and adenitis:• Raised WBC count, ESR and CRP during febrile episodes• High serum IgD > 100u/ml, even in between febrile episodes

Treatment No role of NSAIDs, Antibiotics and antiviral therapy Oral steroids bring about dramatic resolution of the febrile episode. Tonsillectomy and adenoidectomy – Controversial.

Cyclic Neutropenia

• Autosomal dominant defect of myelopoiesis which occurs due to mutation in the ELA2 (Leukocyte elastase) gene.

• Periodic but transient disappearance of granulocytes from circulation. Bone marrow shows early granulocyte precursors.

• Type of Quantitative phagocytic abnormality

Clinical features Fever usually high grade with clockwork periodicity Aphthous oral ulcers, pharyngitis and lymphadenopathy Skin and soft tissue infections are seen during the period of

granulocytopenia

Investigations Absolute neutrophil count is found to be less than 200 cells/cmm

for 3-5 days Count increases thereafter to 2000/cmm till the next neutropenic

period Bone marrow – Early myeloid precursors are present but post

mitotic neutrophils are absent

Treatment• Alternate day steroids• Good response to therapy with recombinant granulocyte

colony-stimulating factor. • Hematopoietic stem cell transplant (HSCT) is the only

alternative therapy for individuals who are refractory to high-dose G-CSF or who undergo malignant transformation.

Prognosis • Most cases can be successfully treated with medications

Familial mediterranean fever

• Most prevalent periodic fever syndrome with irregular episodes

• Autosomal recessive disease with mutation of MEFV gene. 152 mutations have been identified out of which 5 most common ones are M694V, M6801, V726A, M6941 and E148Q.

• Severe disease pattern seen with homozygosity for M694V mutation.

Clinical features Age – 2/3rd have a manifestation before 10 years,

90% of the cases before the age of 20 years. Triggers – Stress, menstruation, exercise and diet. Short attacks of fever, rarely above 39oC. Serositis – Peritonitis, pleuritic or arthritis. Erysipelas like rash mainly on the ankles, shin or feet. Repeated inflammation leads to amyloidosis of kidney,

intestine, liver and spleen

Investigation Acute phase reactants – CRP, ESR, fibrinogen, IL-6,

TNF-alpha are elevated. Amyloid A protein elevated during febrile episode. Genetic testing is confirmatory.

Treatment Colchicine is the first line treatment since 1972. Lifelong therapy is important as discontinuation results in

recurrence. Anakinra (IL-1 receptor antagonist) used in colchicine

resistant cases

Erysipelas like rash seen in FMF

Prognosis Determined by presence or absence of AA amyloidosis

as amyloidosis is the cause of death in most cases in age over 40 years.

Asymptomatic children with known FMF mutation should undergo regular urine analysis for proteinuria as they have increased risk of developing amyloidosis.

Hyper IgD periodic fever syndrome or Mevalonate Kinase Deficiency

•Autosomal recessive disease caused by mutation in mevalonate kinase (MVK) gene on long arm of chromosome 12 resulting in significant reduction of MVK activity.

•Deficiency of mevalonate kinase enzyme causes increased interleukins leading to inflammation.

•16 mutations of MVK have been identified among which V3771 is the most common.

Clinical features Age – Usually within first year of life. Race – Whites, especially from western European countries Attacks triggered by – Immunisation, injury or stress Febrile episode is heralded by chills followed by a sharp rise

in temperature for 4 to 6 days with gradual defervescence. Associated with tender firm lymphadenopathy mainly cervical. Hepatomegaly and splenomegaly. Less commonly – Arthralgia, arthritis, recurrent aphthous oral

or genital ulcers and skin rash Patients are well in between attacks with no growth

impairment.

Investigation Acute phase reactants – CRP and ESR are raised during febrile

attack. High levels of serum IgD more than 200mg/ml ( not specific for

HIDS, seen in 10-30% of TRAPS and FMF) Raised IgA levels are seen during attack in 80% of the cases.

Treatment Etanercept (Anti-TNF factor alpha) and anakinra ( IL-1 receptor

antagonist) bring about improvement during attack.

Prognosis Frequency highest in childhood and adolescent but gradually

decreases as age advances.

Tumor necrosis factor receptor associated periodic syndrome (TRAPS)

• Previously known as familial Hibernian fever first described in 1982.

• Second most common periodic fever. • Autosomal dominant disorder caused by mutation in the

TNFRSF1A on chromosome 12p13.• 50 mutations have been identified.

Clinical features

Age – Usually presents before 4 years of age although it may vary from few weeks to 40 years of age.

Gender – Boys and girls equally affected. Fever – high grade, more than 40o C lasting for more

than 7 days. Severe localised pain and tightness of muscle which

becomes migratory in nature.

• Arthralgia – Can be mono or oligo-articular involving knee, shoulder or elbow.

• Skin rashes – Erythematous macules or plaques simulating cellulitis.

• Periorbital oedema and painful conjunctivitis.

• Less common – Mouth ulcers, abdominal and testicular pain and CNS manifestations.

Investigations Neutrophilia, thrombocytosis with raised CRP, ESR and

complement activation. Elevated serum immunoglobulins including IgA and IgD.

Treatment High doses of steroids at the beginning of attack

reduces severity Etanercept, anti-TNF alpha is highly effective