Overview
Definition:
Periodic fever syndromes (PFS) are a group of rare inherited or acquired disorders characterized by recurrent episodes of fever and inflammation, often without an obvious infectious cause
PFAPA (Periodic Fever, Aphthous stomatitis, Pharyngitis, Adenitis) is the most common autoinflammatory syndrome in children and is typically benign and self-limiting
Monogenic autoinflammatory diseases (MAIDs) encompass a broader spectrum of inherited inflammatory disorders caused by mutations in single genes involved in innate immunity, leading to dysregulated cytokine production and systemic inflammation.
Epidemiology:
PFAPA is estimated to occur in 1.1 to 4.1 per 100,000 children, with a peak onset between 2 and 5 years of age
It is more common in males
MAIDs are rare, with varying prevalence depending on the specific syndrome, and can affect individuals of all ages, though many present in childhood
Familial Mediterranean Fever (FMF) is the most common MAID worldwide, particularly in Mediterranean and Middle Eastern populations.
Clinical Significance:
Accurate differentiation between PFAPA and MAIDs is crucial for appropriate management and to avoid unnecessary investigations or treatments
PFAPA, while benign, can cause significant parental anxiety and missed school days
MAIDs, if untreated, can lead to severe systemic complications including amyloidosis, arthritis, vasculitis, and organ damage, necessitating prompt diagnosis and targeted therapy.
Pfapa Syndrome
Definition:
PFAPA is a clinical diagnosis characterized by recurrent episodes of fever accompanied by aphthous stomatitis, pharyngitis, and cervical adenitis.
Epidemiology:
Peak onset between 2-5 years
more common in males
typically sporadic
familial clustering can occur but not due to known monogenic defects.
Clinical Features:
Recurrent episodes of fever (38.5°C or higher) lasting 3-7 days
Episodes occur at predictable intervals (e.g., every 2-6 weeks)
Associated symptoms include: aphthous stomatitis (small, painful ulcers on oral mucosa)
pharyngitis (sore throat)
cervical adenitis (swollen, tender neck lymph nodes)
Other symptoms may include malaise, headache, abdominal pain, vomiting, diarrhea, and occasionally rash
During febrile episodes, patients appear ill but are typically well between episodes
Absence of significant systemic signs of inflammation between episodes is characteristic.
Diagnostic Criteria:
Magaroni criteria: 1
Recurrent fever episodes of >3 days duration
2
Presence of aphthous stomatitis, pharyngitis, or cervical adenitis
3
Afebrile intervals of normal health lasting weeks to months
4
Normal physical examination between episodes
5
Age of onset < 5 years
6
Exclusion of other causes of recurrent fever
Laboratory findings typically show elevated inflammatory markers (ESR, CRP) during febrile episodes, which normalize between episodes
No specific genetic marker is identified.
Monogenic Autoinflammatory Diseases
Definition:
MAIDs are a group of disorders caused by germline mutations in genes involved in innate immune regulation, leading to uncontrolled inflammatory responses.
Classification:
Categorized based on the primary affected pathway, e.g., pyrinopathies (Familial Mediterranean Fever - FMF, TRAPS), inflammasomopathies (NOMID/CINCA, CAPS), IL-1 pathway dysregulation (HIDS/MKD, CANDLE syndrome), interferonopathies (STING-associated vasculopathy with onset in childhood - SAVI).
Common Syndromes:
Familial Mediterranean Fever (FMF), Tumor Necrosis Factor Receptor Associated Periodic Syndrome (TRAPS), Hyperimmunoglobulin D Syndrome (HIDS) / Mevalonate Kinase Deficiency (MKD), Neonatal Onset Multisystem Inflammatory Disease (NOMID)/Chronic Infantile Neurological Cutaneous and Articular (CINCA) syndrome (part of CAPS), Deficiency of Interleukin-1 Receptor Antagonist (DIRA).
Genetic Basis:
Caused by mutations in genes such as MEFV (FMF), TNFRSF1A (TRAPS), MVK (HIDS/MKD), NLRP3 (CAPS), IL1RN (DIRA)
Genetic testing is crucial for definitive diagnosis.
Diagnostic Approach
History Taking:
Detailed history of fever episodes: frequency, duration, timing, intensity
Associated symptoms during fever: sore throat, mouth ulcers, rash, joint pain, abdominal pain, eye redness
Interval health: well or symptomatic between episodes
Family history of recurrent fevers, autoimmune diseases, or unexplained inflammation
Past medical history, including any prior diagnoses or treatments
Red flags: prolonged fevers (>7 days per episode), symptoms suggestive of specific organ involvement (e.g., joint swelling, rash, abdominal pain suggestive of serositis, neurological symptoms), persistent inflammation between episodes, early onset (<1 year).
Physical Examination:
Systematic examination focusing on: Oropharyngeal assessment (aphthous ulcers)
Neck lymph nodes
Skin examination (rashes, purpura)
Joint examination (swelling, tenderness)
Ophthalmic examination (conjunctivitis, uveitis)
Abdominal examination (organomegaly, tenderness)
Neurological assessment
Examination between febrile episodes is critical to identify subtle chronic inflammation.
Investigations:
Complete Blood Count (CBC) with differential: may show leukocytosis during flares
Erythrocyte Sedimentation Rate (ESR) and C-Reactive Protein (CRP): elevated during flares, normalized between
Blood cultures: to rule out infection
Serum ferritin: elevated in some MAIDs
Autoantibody screen (ANA, RF, ANCA): typically negative in PFAPA, may be positive in some MAIDs
Inflammatory markers (IL-6, IL-1β): useful in specific MAIDs
Genetic testing: essential for confirming MAIDs (MEFV, TNFRSF1A, MVK, NLRP3, IL1RN genes)
Imaging: Ultrasound of lymph nodes if significantly enlarged
Other imaging based on suspected organ involvement.
Differential Diagnosis:
Infectious causes (viral exanthems, bacterial infections, recurrent sinusitis)
Other autoinflammatory syndromes (BLyS, etc.)
Periodic Neutropenias
Juvenile Idiopathic Arthritis (JIA)
Systemic Lupus Erythematosus (SLE)
Vasculitis
Malignancy
Cyclic neutropenia
Cyclic thrombocytopenia.
Management
Pfapa Management:
Observation and reassurance for most cases as PFAPA is self-limiting
Symptomatic treatment: antipyretics (paracetamol, ibuprofen)
Tonsillectomy: considered for severe or prolonged episodes impacting quality of life
often curative
Single dose of Prednisolone (1-2 mg/kg orally) at the onset of fever can abort an episode but may shorten the interval between episodes and is not a long-term solution.
Maid Management:
Targeted therapy based on the specific MAID and affected pathways
Anti-inflammatory agents: NSAIDs for mild symptoms
Corticosteroids: for acute flares, generally short-term
Biologics targeting specific cytokines: Anakinra (IL-1 receptor antagonist) for CAPS, DIRA, TRAPS
Canakinumab (IL-1β inhibitor) for CAPS
Etanercept (TNF-α inhibitor) for TRAPS
Rilonacept (IL-1 trap) for CAPS
Colchicine: cornerstone for FMF to prevent amyloidosis and reduce attack frequency
Methotrexate: sometimes used in specific MAIDs or for associated autoimmune phenomena
Genetic counseling and family screening.
Supportive Care:
Nutritional support during febrile episodes
Hydration
Pain management
Psychosocial support for patients and families
Regular monitoring for disease progression and complications
Patient education on disease course and management.
Complications
Pfapa Complications:
Generally benign with no long-term sequelae
Rarely, chronic tonsillitis or adenitis may persist
Psychosocial distress for patient and family due to recurrent illness and missed school/work.
Maid Complications:
Amyloidosis (especially secondary to FMF) leading to renal, gastrointestinal, and other organ damage
Chronic arthritis and joint destruction
Vasculitis
Stroke
Myocardial infarction
Ocular inflammation leading to vision loss
Hearing loss (in NOMID/CINCA)
Neurological damage (in NOMID/CINCA)
Increased risk of infections due to immunosuppression from treatment.
Prevention Strategies:
For PFAPA: Tonsillectomy may prevent future episodes
For MAIDs: Early diagnosis and consistent treatment with appropriate biologics or colchicine are key to preventing organ damage and chronic complications
Regular follow-up and monitoring are essential.
Prognosis
Pfapa Prognosis:
Excellent
most children outgrow PFAPA by late adolescence
Quality of life improves significantly after tonsillectomy if performed.
Maid Prognosis:
Variable depending on the specific MAID, genetic mutation, and promptness/effectiveness of treatment
With optimal management, many patients can achieve remission and prevent long-term complications
Untreated or poorly managed MAIDs have a guarded prognosis with significant morbidity and mortality.
Follow Up:
For PFAPA: Routine follow-up generally not required after resolution or tonsillectomy, unless new symptoms arise
For MAIDs: Lifelong follow-up is essential
Regular clinical assessments, laboratory monitoring (inflammatory markers, renal function, liver function), and assessment for complications like amyloidosis are crucial.
Key Points
Exam Focus:
Differentiate PFAPA from MAIDs based on clinical features and investigations
Recognize the characteristic triad of PFAPA: fever, aphthous stomatitis, pharyngitis, adenitis
Understand the typical periodicity of PFAPA episodes
Key MAIDs: FMF (colchicine treatment, amyloidosis risk), CAPS (IL-1 blockade), TRAPS (TNFRSF1A mutations, EPO therapy)
Genetic testing is definitive for MAIDs.
Clinical Pearls:
A child with recurrent fevers, aphthous ulcers, sore throat, and swollen neck nodes, who is well between episodes and has normal inflammatory markers between flares, strongly suggests PFAPA
Consider MAID if fever is prolonged (>7 days), atypical symptoms are present, or there is a strong family history
Always check inflammatory markers (ESR, CRP) during and between episodes
Do not miss the risk of amyloidosis in FMF
colchicine is life-saving.
Common Mistakes:
Misdiagnosing PFAPA as recurrent viral infections and delaying appropriate management
Over-treating PFAPA with antibiotics
Failing to investigate for MAIDs in children with unexplained recurrent fevers, especially if there are concerning features
Inadequate follow-up for patients with MAIDs, leading to preventable complications
Prescribing steroids long-term for PFAPA.