Why my Child, Keeps Getting Fevers?

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Dr .Hesham Farouk

 Specialist Pediatrician  -Aster Clinic Discovery Gardens & Arabian ranches

    Mother Asking: Every few weeks my toddler will develop a fever that lasts a couple of days but then goes away. Other than the fever, she doesn’t have any other symptoms. Could it be periodic fever syndrome? How is that diagnosed, and is treatment for it different than treating a “normal” fever in kids?



    ANSWER: From your description, it sounds like your child could have periodic fever syndrome. Make an appointment with her doctor to have the condition evaluated. A diagnosis of periodic fever syndrome is based on symptoms. Effective treatment is available.
     Periodic fever syndromes (PFS) are a group of rare autoinflammatory diseases characterized by inappropriate, uncontrolled, and often spontaneous signs and symptoms of inflammation. Recurrent fever ≥
38°C is the cardinal feature in each PFS. The recurrent febrile episodes occur in the absence of infection or evidence of active autoimmunity. Fevers in PFS are due to abnormalities in activation of the innate immune system.
    In general, children with these syndromes are well between episodes. Many of these syndromes are hereditary (passed down from parents) and result from a mutation (defect or mistake) in a gene (this is the code that determines the structure of our proteins). The syndromes are defined by several factors, including:


  • The gene defect
  • The clinical features of the syndrome
  • The parts of the body affected in addition to the fever
  • The age of the child when the syndrome starts
  • The ethnicity (the area of the world where the child or parents come from) of the child and parents
Many of these syndromes have a specific treatment, often based on understanding the problem caused by the genetic defect.

 

Causes:

   Classification of periodic fever syndromes

 

1)Hereditary PFS:

    • Familial Mediterranean fever (FMF)






  • Hyperimmunoglobulinemia D with periodic fever syndrome (HIDS)
  • Tumor necrosis factor (TNF) receptor associated periodic syndrome (TRAPS)
  • Cryopyrin-associated periodic syndromes (CAPS):
    Muckle-Wells syndrome (MWS)
    Neonatal onset multisystem inflammatory disorder (NOMID) or chronic infantile neurologic cutaneous and articular syndrome (CINCA)
  • Familial cold autoinflammatory syndrome (FCAS)

 

2)Idiopathic PFS:




  • Periodic fever with aphthous stomatitis, pharyngitis and adenitis (PFAPA syndrome)
Inheritance pattern of hereditary periodic fever syndromes

 

3)Autosomal Dominant

  • TNF receptor-associated periodic syndrome (TRAPS)
  • Cryopyrin-associated periodic syndromes: NOMID/CINCA, MWS, FCAS

4)Autosomal Recessive

  • Familial Mediterranean fever (FMF)
  • Hyperimmunoglobulinemia D with periodic fever syndrome (HIDS)

What other disease/condition shares some of these symptoms?

  • Cyclic neutropenia
  • Fever of unknown origin
  • HIV/AIDS



  • Tuberculosis, cytomegalovirus (CMV), brucellosis, rat-bite fever, relapsing fever or other chronic viral, bacterial or parasitic infections
  • Systemic lupus erythematosus, relapsing polychondritis
  • Anti-neutrophil cytoplasmic antibodies (ANCA)-mediated vasculitis, including Wegener’s granulomatosis and microscopic polyangiitis
  • Takayasu’s arteritis

Other systemic autoinflammatory diseases

  • HLA B27-associated juvenile spondyloarthropathies
  • Sarcoidosis
  • Malignancies, including leukemia and lymphoma
  • Autoimmune lymphoproliferative syndrome (ALPS)
  • Acute intermittent porphyria
  • Surgical emergencies, including appendicitis, intussusception, testicular or ovarian torsion
  • Relapsing pancreatitis
Other systemic autoinflammatory syndromes that mimic PFS
  • Systemic onset juvenile idiopathic arthritis, adult Still’s disease
  • Chronic granulomatous synovitis with uveitis and cranial neuropathy (Blau syndrome)
  • Pyogenic arthritis, pyoderma gangrenosum and acne (PAPA) syndrome



  • Behçet’s disease
  • Crohn’s disease
  • Macrophage activation syndrome
  • Hereditary or acquired angioedema
  • Gout
  • Autoinflammatory bone diseases:
    CRMO (chronic recurrent multifocal osteomyelitis)
    SAPHO (synovitis, acne, pustulosis, hyperostosis, osteitis)
    Chronic recurrent multifocal osteomyelitis and congenital dyserythropoietic anemia (Majeed syndrome)
    Deficiency of the IL-1 receptor antagonist (DIRA)

 

  • Periodic Fever, Aphthous Stomatitis, Pharyngitis, Adenitis (PFAPA) Syndrome:

  PFAPA is probably the most common disorder. It often appears in early childhood (between the ages of 2 and 5). Children have recurrent episodes of fever, mouth sores, sore throat, and swollen lymph nodes in the neck. There tend to be regular intervals between episodes. There are no long-term complications associated with PFAPA, and treatment is recommended to minimize or eliminate symptoms and allow a return to regular activities. PFAPA may last for several years, but it often goes away on its own during the second decade of life.
  • Familial Mediterranean Fever (FMF):

This genetic disease mostly affects people of Mediterranean and Middle Eastern descent. It causes recurrent fevers along with pain and swelling in the abdomen, chest, or joints. Painful, severe joint swelling can make it hard to walk. It typically affects children before the age of 10. Left untreated, FMF may result in a dangerous buildup of proteins, called amyloidosis, that may lead to organ failure.
Tumor Necrosis Factor Receptor-Associated Periodic Syndrome (TRAPS)
This condition causes intermittent fevers plus a painful rash, chills, and muscle pain. Onset is often in childhood but may be delayed until mid-adulthood. In addition to symptoms common to other periodic fever syndromes, people with TRAPS often have associated eye symptoms including conjunctivitis and swelling around the eye. Amyloidosis may occur in some people.




  • Hyperimmunoglobulin D Syndrome (HIDS):

This rare genetic condition is also known as Mevalonate Kinase-Associated Periodic Fever Syndrome. Symptoms usually start in the first year of life. It typically begins with an abrupt onset of high fever (up to 104). Associated symptoms may include skin rash, abdominal pain, vomiting, diarrhea, joint pain, and swollen neck glands.

 

What laboratory studies should you request to help confirm diagnosis? How should you interpret the results?

 

Initial screening tests:



  • CBC, differential during fever and when symptom-free
  • ESR, CRP during fever and when symptom-free
  • Complete metabolic panel
  • Uric acid, lactate dehydrogenase (LD)
  • Ferritin, fibrinogen
  • Quantitative immunoglobulins (IgG, IgA, IgM)
  • Urinalysis
  • Blood, urine, throat cultures
  • PPD

Additional tests as needed:

  • IgD
  • Cytomegalovirus (CMV), Epstein-Barr virus (EBV), Brucella IgM and IgG
  • CMV, EBV DNA PCR
  • Antinuclear antibody (ANA) panel, anti-neutrophil cytoplasmic antibodies (ANCAs)
  • Angiotensin-converting enzyme (ACE)
  • C3, C4, C1 inhibitor activity
  • HLA typing (specifically for HLA B27, B51)
  • Analysis of synovial fluid for cell count, crystals, and culture
  • 24-hour urine collection for protein and creatinine clearance
  • Bone marrow aspirate and biopsy for histology, cytogenetics, cultures

 

Confirmatory tests:

  • Genotyping for FMF, HIDS, TRAPS, CAPS
  • Renal or rectal biopsy and staining for amyloid deposition

Interpretation of results:

  • Marked leukocytosis with left shift in association with ESR >80 and CRP >80 suggest infection.
  • Positive IgM serologies, PCR or cultures suggest infection.
  • Elevated ACE suggests sarcoidosis.
  • Positive PPD suggests tuberculosis.
  • Elevated uric acid, especially if there is associated leukocytosis or thrombocytopenia, suggests leukemia.
  • ANA ≥1:320, positive lupus serologies, or ANCA suggests possible systemic autoimmune disease.
  • Hypogammaglobulinemia suggests infection secondary to a primary immunodeficiency.
  • Hypergammaglobulinemia suggests HIV or systemic autoimmune disease.
  • Suspect HIDS if elevated serum IgD with or without elevated IgA and normal IgG and IgM.

Would imaging studies be helpful? If so, which ones?

    • Chest x-ray can be helpful when infection, inflammatory lung disease, or serositis (pleuritis, pericarditis) is suspected.
    • Abdominal x-rays or ultrasound may be indicated to evaluate abdominal pain, or help rule out peritonitis or a surgical emergency.
    • CT scan of the neck, chest, abdomen or pelvis may be needed to evaluate lymphadenopathy, inflammatory lung disease, serositis, or splenomegaly.




  • Echocardiogram is indicated to evaluate chest pain and rule out pericarditis.
  • Consider bone gallium scan to rule out osteomyelitis.
  • Consider joint MRI with and without contrast for arthritis.
  • Consider head MRI with and without contrast, and MRA to evaluate for CNS vasculitis and causes of headache, developmental delay, or hearing loss.

Confirming the diagnosis

 



  • Pertinent history:

Document recurrent episodes of fever ≥38°C.
FOR at least 4-12 months.
WITHOUT concurrent infectious symptoms.

Fever characteristics:

  • Peak fever temperature
  • Pattern of fever (hectic, quotidian, recurrent, relapsing/periodic, continuous, intermittent, remittent)
  • Duration of fever
  • Antecedent or prodromal symptoms prior to onset of fever
  • Associated symptoms (rash, arthritis, diarrhea, etc.)
  • Pattern of appearance of associated symptoms
  • Duration of associated symptoms
  • Predictability of symptoms and illness course
  • Duration of fever-free intervals
  • Overall health and persistent or chronic symptoms when afebrile
  • Family history of similar febrile illnesses and response to treatment
  • Ethnicity of parents
  • Number and type of infections in lifetime and response to antibiotics.

 

Suspect diagnosis of PFS if:

  • Recurrent fevers without history of infectious symptoms or response to antibiotics.
  • Fever-free intervals of generally good health.
  • Family history, especially in first degree relative, of similar symptoms
  • Amyloidosis, chronic uveitis, hearing loss, serositis, or arthritis are also present.
If you are able to confirm that the patient has a periodic fever syndrome, what treatment should be initiated?
  • Therapies that should be instituted immediately are shown in Table I.
Table I.
FMF
Colchicine 1 mg p.o. daily regardless of age or weightIntravenous fluids as neededIf significant serositis: consider prednisone 0.5-2 mg/kg/day or methylprednisolone 10-30 mg/kg (max 1 gm) IV daily times 1-3 doses; taper and discontinue with symptomatic improvementAvoid unnecessary surgery
TRAPS
NSAIDs for pain: Naproxen 10 mg/kg b.i.d.; celecoxib 50-100 mg b.i.d.; meloxicam 0.125 mg/kg (max 15 mg) daily; or indomethacin 1 mg/kg b.i.d.Consider prednisone 0.5-2 mg/kg/day for severe symptoms, taper and discontinue with symptomatic improvement or methylprednisolone 10-30 mg/kg (max 1 gm) IV daily times 1-3 days
HIDS


Avoid unnecessary surgeryNSAIDS for fever or pain: Naproxen 10 mg/kg b.i.d.; celecoxib 50-100 mg b.i.d.; meloxicam 0.125 mg/kg (max 15 mg) daily; or indomethacin 1 mg/kg b.i.d.For severe or NSAID-resistant symptoms: Consider prednisone 0.5-2 mg/kg/day, taper and discontinue with symptomatic improvement or methylprednisolone 10-30 mg/kg (max 1 gm) IV daily times 1-3 days
NOMID



IL-1 blockade:Rilonacept 4.4 mg/kg (max 320 mg) SQ on day 1, then 2.2 mg/kg (max 160 mg) SQ q.wk, ORCanakinumab 150 mg SQ q.8 wk if >4 yr & >40 kg or 2-3 mg/kg (max 150 mg) SQ q.8 wk if <40 kg, ORAnakinra 1-10 mg/kg (max 300 mg) SQ dailyNSAIDS: Naproxen 10 mg/kg b.i.d.; celecoxib 50-100 mg b.i.d.; meloxicam 0.125 mg/kg (max 15 mg) daily; or indomethacin 1 mg/kg b.i.d.Consider prednisone 0.5-2 mg/kg/day for severe symptoms; taper and discontinue with symptomatic improvementOmeprazole 10-20 mg daily
FCAS
Cold avoidance
MWS
IL-1 blockade:Rilonacept 4.4 mg/kg (max 320 mg) SQ on day 1, then 2.2 mg/kg (max 160 mg) SQ q.wk, ORCanakinumab 150 mg SQ q.8 wk if >4 yr & >40 kg or 2-3 mg/kg (max 150 mg) SQ q.8 wk if <40 kg, ORAnakinra 1-3.5 mg/kg (max 300 mg) SQ dailyPrednisone 0.5-2 mg/kg/day for severe symptoms; taper and discontinue with symptomatic improvementNSAIDs: Naproxen 10 mg/kg b.i.d.; celecoxib 50-100 mg b.i.d.; or meloxicam 0.125 mg/kg (max 15 mg) dailyOmeprazole 10-20 mg daily
FPAPA None
  • Table II lists longer term treatment for periodic fever syndromes.
Table II.
FMF
Colchicine 0.3-1.8 mg a day depending on mutation genotyping
TRAPS
NSAIDS alone for mild symptomsPrednisone 0.5-2 mg/kg/day for chronic symptomsEtanercept 0.4-1 mg/kg (max 25 mg) SQ 2-3 times wk or 0.8-1 mg/kg (max 75 mg) SQ q.wk for severe symptoms
HIDS
NSAIDSPrednisone 0.25-2 mg/kg/day for chronic symptoms or bursts as needed (often no benefit)IL-1 blockade: Anakinra 1-2 mg/kg (max 100 mg) SQ daily at symptom onset as needed or chronically OR TNF inhibition: Etanercept 0.4-1 mg/kg (max 25 mg) SQ 2-3 times a wk or 0.8-1 mg/kg (max 75 mg) SQ q.wk.
NOMID
Continuous IL-1 blockade:Rilonacept 4.4 mg/kg (max 320 mg) SQ on day 1, then 2.2 mg/kg (max 160) mg SQ q.wk ORCanakinumab 150 mg SQ q.8 wk (>4y & >40 kg); 2-3 mg/kg (max 150 mg) SQ q.8 wk (<40 kg) ORAnakinra 1-6 mg/kg (max 300 mg) SQ dailyNSAIDsOmeprazole 10-20 mg q.day-b.i.d.
FCAS
Cold avoidanceNSAIDS alone if minimal symptomsIntermittent or chronic IL-1 blockade:Rilonacept 4.4 mg/kg (max 320 mg) SQ on day 1, then 2.2 mg/kg (max 160) mg SQ q.wk ORCanakinumab 150 mg SQ q.8 wk (>4 y & >40 kg); 2-3 mg/kg (max 150 mg) SQ q.8 wk (<40 kg)ORAnakinra 0.5-1.5 mg/kg (max 100 mg) SQ daily
MWS
Continuous IL-1 blockade:Rilonacept 4.4 mg/kg (max 320 mg) SQ on day 1, then 2.2 mg/kg (max 160 mg) SQ q.wk ORCanakinumab 150 mg SQ q.8 wk (>4 y & >40 kg); 2-3 mg/kg (max 150 mg) SQ q.8 wk (<40 kg) ORAnakinra 1-3.5 mg/kg (max 300 mg) SQ daily
FPAPA



No treatmentPrednisone 1-2 mg/kg/day (max 60 mg) times 1-2 days at onset of symptomsConsider cimetidine 20-40 mg/kg/dayConsider tonsillectomy (controversial as first-line treatment)
  • Table III lists alternative treatments if standard therapy fails.
Table III.
FMF IL-1 blockade:Anakinra 1-2 mg/kg (max 100 mg) SQ daily ORCanakinumab 150 mg SQ q.8 wk (>4 y & >40 kg); 2-3 mg/kg (max 150 mg) SQ q.8 wk (<40 kg)Thalidomide 100-300 mg daily if IL-1 blockade does not remit symptoms
TRAPS IL-1 blockade: Anakinra 1-2 mg/kg (max 100 mg) SQ daily ORIL-6 blockade: Tocilizumab 4-12 mg/kg IV q.2-4 wk
HIDS Other IL-1 blockade: Rilonacept 4.4 mg/kg (max 320 mg) SQ on day 1, then 2.2 mg/kg (max 160 mg) SQ q.wk ORCanakinumab 150 mg SQ q.8 wk (>4 y & >40 kg); 2-3 mg/kg (max 150 mg) SQ q.8 wk (<40 kg) TNF blockade: Infliximab 3-7.5 mg/kg IV q.4-8 wk Consider simvastin 10-20 mg (max 80 mg) daily ORColchicine 0.3-1.2 mg daily (controversial) ORAzathioprine 1-2 mg/kg/day (max 150-200 mg)Cyclosporine 1-3 mg/kg/day for trough level 100-200 ng/ml
NOMID TNF blockade: Infliximab 5-10 mg/kg IV q.4-8 wkConsider thalidomide 100-300 mg daily
FCAS TNF blockade: Infliximab 3-7.5 mg/kg IV q.4-8 wk
MWS TNF blockade: Infliximab 3-10 mg/kg IV q.4-8 wk
FPAPA Intermittent IL-1 blockade: Anakinra 1 mg/kg (max 100 mg) SQ within 48 hr of attack onset; may repeat onceColchicine 0.3-1.2 mg dailyTonsillectomy
  • Table IV gives advantages and disadvantages of the medication options for treating periodic fever syndromes.
Table IV
Drug Advantages Disadvantages
Anakinra Recombinant IL-1 antagonist that competitively inhibits binding of IL-1 to cell-surface IL-1 receptor, thereby blocking IL-1 activity Daily painful injections; short-term efficacy without long-term benefit after discontinuation
Rilonacept Recombinant IL-1 decoy receptor that binds IL-1 before it can bind to cell surface receptor Weekly injections; relatively new without long-term safety data
Canakinumab Monoclonal Ab to IL-1 that blocks IL-1 activity Every 8 wk injections; relatively new without long-term safety data
Etanercept Soluble TNF receptor that binds TNF before it can bind to cell surface receptor Biweekly or weekly injections; best long-term safety profile
Infliximab Monoclonal Ab to TNFalpha that blocks its activity; long-term safety data available Frequent infusion reactions; requires medical setting to administer; adverse reactions fairly common; safety data known

What are the adverse effects associated with each treatment option?

 

Table V gives the adverse effects associated with each treatment option for periodic fever syndromes.

Table V

NSAIDS Gastritis, gastric ulcer, gastroesophageal reflux, rash, edema, liver/renal toxicity uncommon in children
Corticosteroids Infection, weight gain, muscle atrophy, adrenocortical insufficiency, osteopenia, growth delay, avascular necrosis, emotional lability, rash, edema, hypertension, diabetes
Colchicine Nausea, vomiting, diarrhea, abdominal pain, anorexia, peripheral neuropathy, muscle weakness, rhabdomyolysis, renal/liver toxicity, rash
Etanercept Infection, injection site reaction, CNS/demyelinating disorder, ANA positivity, malignancy (very low risk)
Infliximab Infection (risk > etanercept), allergic reaction, anaphylaxis, nausea, diarrhea, abdominal pain, fatigue, elevated LFTs, serum sickness, ANA positivity, CNS/demyelinating disease, increased heart failure, cytopenias, future malignancy (risk > etanercept)
Anakinra Infection, severe injection site reaction/pain, future malignancy
Rilonacept Infection, injection site reaction, hypersensitivity reaction, hyperlipidemia, ? future malignancy
Canakinumab Infection, injection site reaction, diarrhea, nausea, vertigo, weight gain, myalgias, headache, future malignancy
Tocilizumab Infection, thrombocytopenia, allergic reaction, anaphylaxis, CNS/demyelinating disorder, GI perforation, elevated LFTs, hyperlipidemia, future malignancy
Azathioprine Infection, leukopenia, pancytopenia with low thiopurine S-methyl transferase (TPMT) activity, liver toxicity, nausea, vomiting, secondary malignancy
Simvastatin Constipation, dyspepsia, rhabdomyolysis, hepatitis, acute renal failure
Cimetidine Headache, cytopenias
Thalidomide Infection, peripheral neuropathy, somnolence, teratogenicity, rash, dizziness, mood changes
Cyclosporine Infection, hypertension, renal toxicity, renal failure, hirsutism, GI upset, malignancy, CNS toxicity, gingival hyperplasia
Tonsillectomy Pain/risks from surgery

What are the possible outcomes of periodic fever syndromes?

 

There are some significant morbidities and increased mortality rates seen in untreated patients with inherited PFS:

 

  • Cryopyrin-associated periodic syndromes, CAPS (FCAS, MWS, NOMID/CINCA):

 

Each of these syndromes are due to an autosomal dominant mutation in a single gene, NLRP3. Phenotypes and complications are different among FCAS, MWS, and NOMID, although significant overlap is noted. All share a characteristic urticarial rash, but fever may or may not be present. The most severe disease is seen in NOMID, followed by MWS and FCAS. The frequency of 2° amyloidosis is greatest in MWS, followed by NOMID and then FCAS.

 

  • FCAS (Familial cold autoinflammatory syndrome):

Usually diagnosed at birth or within first 6 months of life, based on attacks of urticarial rash and fever triggered by cold exposure and lasting less than 24 hrs. These patients usually have a normal lifespan, but 2° amyloidosis occurs in up to 5% of patients. Daily fatigue, headache, and myalgias, even without cold exposure, contribute to considerable morbidity.

 



  • MWS (Muckle-Wells syndrome):




Characterized by recurrent but unpredictable attacks of fever >38.5°C and urticaria lasting for 1-3 days, although some symptoms may persist. The age of onset is often <6 months, and triggering by cold is not necessary. MWS was originally described as a triad of urticaria, deafness and amyloidosis, but only 25% patients with identifiable NLRP3 mutations develop amyloidosis. Conjunctivitis (in >90%) and progressive sensorineural hearing loss (>70%) are pathognomonic. Since the fever pattern is less predictable than in FCAS, the diagnosis of MWS is often delayed until hearing loss is noted during adolescence. All patients suffer from severe chronic fatigue, which remits with IL-1 blockade. Abdominal pain and headaches occur in most patients during fevers, but these are not as severe as in FMF. Arthralgias are more common than chronic arthritis. Recurrent oral aphthae occur in >50% patients during fevers.

 

  • NOMID/CINCA (Neonatal-onset multisystem inflammatory disease / chronic infantile neurological cutaneous articular syndrome):

 

This is the most severe form of CAPS, with chronic urticaria with or without fever noted at birth or in the newborn period. Continuous symptoms and frequent flares are not necessarily accompanied by fever. Unlike other PFSs, NOMID follows a chronic course with significant complications, poor overall prognosis and shortened lifespan if untreated (by IL-1 blockade therapy.) Early diagnosis and treatment with IL-1 inhibition improves quality of life and delays or prevents morbidities. Severe CNS manifestations are seen in 90% of untreated patients. The characteristic epiphyseal overgrowth arthropathy is pathognomonic and develops in 30%-60% of patients. Secondary amyloidosis develops in 10%-25% of patients. Other complications vary in severity and age of onset, but include:
  • ˚ Early growth retardation, delayed puberty
  • ˚ Skull abnormalities, frontal bossing
  • ˚ Progressive profound sensorineural hearing loss from early childhood in >70%.
  • ˚ Chronic aseptic meningitis, often with chronic headache, papilledema, and increased intracranial pressure
  • ˚ Mild arthritis in >65%, but 30%-60% develop early severe chronic joint inflammation with characteristic epiphyseal overgrowth, especially of patellae, with progressive joint contractures and limited mobility
  • ˚ Progressive cognitive impairment.
  • ˚ Chronic intraocular inflammation in 50% manifested by treatment-resistant anterior/posterior uveitis, optic atrophy, and severe vision loss in 25% or blindness.