SUMMARY
1. IL-1 receptor associated kinase-4 (IRAK-4) deficiency is an innate immune deficiency caused by impaired toll-like receptor (TLR) signaling (TLR 2/1, 2/6, 4, 5, 7, 8, and 9). MyD88-independent toll-like receptor signaling (TLR3) is not affected.
2. Patients with IRAK-4 deficiency have recurrent invasive infections (cellulitis, sepsis, meningitis, osteomyelitis) mainly caused by Staphylococcus aureus and Streptococcus pneumoniae. Mortality is as high as 40% in the first decade of life but infections decrease significantly as patients grow older.
3. Patients characteristically lack fevers and signs of inflammation (elevated ESR/CRP) despite active infection.
4. Serum immunoglobulin levels, specific antibody responses, T-cell / B-cell subsets and function are normal.
5. TLR function tests that measure inflammatory cytokine production (IL-6, TNF-alpha, IL-1) after stimulus with TLR ligands will be very depressed.
6. The diagnosis is confirmed by IRAK-4 gene sequencing.
7. Patients are treated with monthly IVIG and prophylactic antibiotics. Vaccination against encapsulated bacteria should be initiated for patients who do not receive IVIG. Therapy should continue at least until the teen years (16 years) when the risk of mortality appears to decrease.
OVERVIEW
IRAK-4 deficiency is an autosomal recessive defect of innate immunity. Patients with this disease are characterized by an increased susceptibility to invasive Staphylococcus aureus and Streptococcus pneumoniae infections. Invasive gram negative bacterial infections have been described in some patients. Patients do not appear to be at risk of fungal, viral, or mycobacterial disease. A unique hallmark of this disease is the lack of fevers and inflammatory response (elevated ESR/CRP) despite severe infections due to an impaired ability to upregulate pro-inflammatory cytokines. Of the patients reported to date, there has been a striking 40% mortality in the first decade of life. However, no deaths were reported after 8 years of age and no invasive bacterial infections occurred after 14 years of age. This improvement is postulated to be the result of adaptive immune maturation that occurs with age. Humoral and cell-mediated immune function is typically normal, although impaired antibody response to polysaccharide antigens have been described in some patients.
PATHOGENESIS
The innate immune system is designed to provide immediate protection from infection unlike the adaptive immune system which requires time to mount a specific response. The innate immune system uses a system of pattern recognition receptors to detect pathogen associated molecular patterns (PAMPs). Toll-like receptors (TLR) are an example of these pattern recognition receptors. Ten human TLRs have been described to date and each TLR is activated by a specific bacterial or viral PAMPs:
TLR 1/2 Bacterial and mycobacterial cell wall
TLR2/6 Bacterial cell wall
TLR 3 Viral double stranded RNA (product of replication in DNA and RNA viruses)
TLR4 LPS of gram negative bacteria
TLR 5 Bacterial flagellin
TLR 7/8 Viral single stranded RNA (Influenza)
TLR 9 Bacterial CpG DNA (Herpes viruses)
After recognition of PAMPs, TLRs trigger intracellular signaling pathways that result in the activation of the key transcription factor NF-kB which upregulates the production of inflammatory cytokines, chemokines, adhesion molecules, antimicrobial peptides, inducible nitric oxide synthetase, and type I interferons. MyD88 and IRAK-4 are essential for all TLR signaling except for TLR3 (TLR4 can signal through MyD88 or MyD88-independent pathways).
Homozygous or compound heterozygous mutations in IRAK-4 cause IRAK-4 deficiency. All mutations described result in a lack of protein expression. TLR signaling in response to bacterial PAMPs is greatly diminished. Because TLR3 signaling is IRAK-4/MyD88 independent, anti-viral defense appears to be preserved.
DIFFERENTIAL DIAGNOSIS
Innate immune defects to consider in addition to IRAK-4 deficiency include the following:
1.MyD88 deficiency
2.X-linked Anhidrotic Ectoderma Dysplasia with Immunodeficiency (NEMO mutations)
3.Autosomal dominant Anhidrotic Ectoderma Dysplasia with Immunodeficiency (IKBA mutations)
EVALUATION
An evaluation for this disease should be considered in the setting of a patient with invasive bacterial infections and poor febrile or inflammatory response.
Step 1: Test TLR Function
-TLR Assay
-This assay is commercially available through ARUP or IBT laboratories.
-This assay would be expected to be abnormal in innate immune defects including IRAK-4 deficiency, MyD88 deficiency, and hypomorphic NEMO mutations.
Step 2: Gene sequencing - this should be considered if the TLR function is decreased
-IRAK-4 gene sequencing
-This testing is commercially available through Gene Dx.
MANAGEMENT
Initiation of treatment is essential given the high rate of mortality in the first decade of life. Therapies should be continued until at least the teenage years when infectious complications become less common. The following regimen is recommended:
1. Monthly immunoglobulin (IVIG) therapy
This therapy should be continued at least until 16 years of age, after which risk for invasive infections and death appear to decrease. A typical starting dose is 400-600mg/kg once a month for the IV form of immunoglobulin.
2. Prophylactic antibiotic therapy
-Amoxicillin 20mg/kg divided twice daily. Maximum 500mg twice daily.
-Trimethoprim-sulfamethoxazol 6 mg/kg (TMP component) divided twice daily.
Maximum one double strength tablet (sulfamethoxazole 800 mg; trimethoprim 160 mg) twice daily.
3. Vaccination
Vaccination with protein-conjugate and polysaccharide vaccines should be initiated if IVIG therapy is not started.
RESOURCES
Diagnostic Resources
1. IBT - Toll-like receptor assay
2. ARUP - Toll-like receptor assay
3. Gene Dx - IRAK-4 gene sequencing
Literature Resources
1. Picard 2007
Update on IRAK-4 deficiency
2. Orange 2006
TLR functional assay
3. Picard 2010
Clinical Features and Outcome in IRAK4 and MyD88 Deficiency