Clinical features and outcome of patients with IRAK-4 and MyD88 deficiency

Abstract

Autosomal recessive interleukin-1 receptor-associated kinase (IRAK)-4 and myeloid differentiation factor (MyD)88 deficiencies impair Toll-like receptor (TLR)- and interleukin-1 receptor-mediated immunity. We documented the clinical features and outcome of 48 patients with IRAK-4 deficiency and 12 patients with MyD88 deficiency, from 37 kindreds in 15 countries.The clinical features of IRAK-4 and MyD88 deficiency were indistinguishable. There were no severe viral, parasitic, and fungal diseases, and the range of bacterial infections was narrow. Noninvasive bacterial infections occurred in 52 patients, with a high incidence of infections of the upper respiratory tract and the skin, mostly caused by Pseudomonas aeruginosa and Staphylococcus aureus, respectively. The leading threat was invasive pneumococcal disease, documented in 41 patients (68%) and causing 72 documented invasive infections (52.2%). P. aeruginosa and Staph. aureus documented invasive infections also occurred (16.7% and 16%, respectively, in 13 and 13 patients, respectively). Systemic signs of inflammation were usually weak or delayed. The first invasive infection occurred before the age of 2 years in 53 (88.3%) and in the neonatal period in 19 (32.7%) patients. Multiple or recurrent invasive infections were observed in most survivors (n = 36/50, 72%).Clinical outcome was poor, with 24 deaths, in 10 cases during the first invasive episode and in 16 cases of invasive pneumococcal disease. However, no death and invasive infectious disease were reported in patients after the age of 8 years and 14 years, respectively. Antibiotic prophylaxis (n = 34), antipneumococcal vaccination (n = 31), and/or IgG infusion (n = 19), when instituted, had a beneficial impact on patients until the teenage years, with no seemingly detectable impact thereafter.IRAK-4 and MyD88 deficiencies predispose patients to recurrent life-threatening bacterial diseases, such as invasive pneumococcal disease in particular, in infancy and early childhood, with weak signs of inflammation. Patients and families should be informed of the risk of developing life-threatening infections; empiric antibacterial treatment and immediate medical consultation are strongly recommended in cases of suspected infection or moderate fever. Prophylactic measures in childhood are beneficial, until spontaneous improvement occurs in adolescence.

Figure 1

Schematic representation of TIRs signaling pathway. MyD88 interacts with TLRs and IL-1Rs through a shared TIR domain. MyD88 is a key cytosolic adapter molecule, providing a bridge from TLRs and IL-1Rs to the 2 active kinases IRAK-4 and IRAK-1. IRAK-4 and IRAK-1 then activate at least the 2 signaling NF-kB and MAPK pathways. The MyD88- and IRAK-4-dependent TIR pathway leads among others to the synthesis of inflammatory cytokines, such as IL-1β, IL-6, IL-8, TNF-α, and to IFN-α/β and IFN-λ, at least for TLR7, TLR8 and TLR9. The MyD88- and IRAK-4-independent TIR pathway uses TRIF pathway after stimulation of TLR3 and TLR4. This pathway is important for IFN-α and IFN-β production.

Figure 2

Pedigrees of the 31 kindreds identified with IRAK-4 deficiency. Each kindred with IRAK-4 deficiency is designated by a capital letter (A-E1) each generation is designated by a Roman numeral (I–IV), and each individual is designated by an Arabic numeral (from left to right). Patients with a clinical phenotype are indicated by closed symbols. Patients with confirmed IRAK-4 deficiency but no clinical phenotype as yet are indicated by an open square divided by a black line. In each family, the proband is indicated by an arrow. Individuals whose genetic status could not be evaluated are indicated by “E?”.

Figure 2

Pedigrees of the 31 kindreds identified with IRAK-4 deficiency. Each kindred with IRAK-4 deficiency is designated by a capital letter (A-E1) each generation is designated by a Roman numeral (I–IV), and each individual is designated by an Arabic numeral (from left to right). Patients with a clinical phenotype are indicated by closed symbols. Patients with confirmed IRAK-4 deficiency but no clinical phenotype as yet are indicated by an open square divided by a black line. In each family, the proband is indicated by an arrow. Individuals whose genetic status could not be evaluated are indicated by “E?”.

Figure 3

Pedigrees of the 6 kindreds with MyD88 deficiency identified. Each kindred with MyD88 deficiency is designated by a lower case letter (a-f) ; each generation is designated by a Roman numeral (I–IV), and each individual is designated by an Arabic numeral (from left to right). Patients with a clinical phenotype are indicated by closed symbols. In each family, the proband is indicated by an arrow. Individuals whose genetic status could not be evaluated are indicated by “E?”.

Figure 4

Countries of origin of the 31 kindreds with IRAK-4 deficiency and the 6 kindreds with MyD88 deficiency identified. The number of patients identified in each country is indicated.

Figure 5

Invasive bacterial infections (episodes): in all patients, in IRAK-4-deficient patients, and in MyD88-deficient patients.

Figure 6

Percentage of clinical manifestations found in each patient: in MyD88-deficient patients, in IRAK-4-deficient patients, and in all patients. (ENT = ear, nose, and throat.)

Figure 7

Overview of pathogens isolated during bacterial infections of IRAK-4-deficient and MyD88-deficient patients. Left column, overview of all pathogens isolated (all documented infection). In IRAK-4-deficient patients: other Streptococcus species ( Str. agalactiae, Str. equis, Str. intermedius, Str. milleri, Str. pyogenes, and Str. parasanguis ), other gram-negative bacteria ( Shigella sonnei, Neisseria meningitidis, Serratia marcesens, Moraxella catarrhalis, Clostridium septicum, Haemophilus influenzae type b, Citrobacter freundii, and Escherichia coli ), and Mycobacterium avium. In MyD88-deficient patients: other Streptococcus species (β-hemolytic Streptococci ) and other gram-negative bacteria ( Salmonella enteritidis, Haemophilus influnzae type e, Moraxella catarrhalis, Klebsiella pneumoniae, and E. coli ). Center column, pathogens isolated during invasive bacterial infections (InvBD) (meningitis, sepsis, arthritis, osteomyelitis, and deep abscesses). In IRAK-4-deficient patients: other Streptococcus species ( Str. agalactiae, Str. milleri, Str. pyogenes, and Str. parasanguis ) and other gram-negative bacteria ( Shigella sonnei, N. meningitidis, Serratia marcesens, H. influenzae type b and C. septicum ). In MyD88-deficient patients: other Streptococcus species (β-hemolytic Streptococci ) and other gram-negative bacteria ( Salmonella enteritidis, H. influenzae type e, and Moraxella catarrhalis ). Right column, pathogens isolated during noninvasive bacterial infections (NinvBD). In IRAK-4-deficient patients: other Streptococcus species ( Str. equis, Str. intermedius, Str. pyogenes ) and other gram-negative bacteria ( Serratia marcesens, Moraxella catarrhalis, C. septicum, Citrobacter freundii, and E. coli ), and M. avium. In MyD88-deficient patients: other Streptococcus species (β-hemolytic Streptococci ) and other gram-negative bacteria ( K. pneumoniae and E. coli ).

Figure 8

Epidemiologic features of IRAK-4 and MyD88 deficiency. Incidence of first bacterial infection in IRAK-4-deficient and MyD88-deficient patients during the first 50 months of life. (wo = without, pts = patients.)

Figure 9

Annual rate of bacterial infections per patient, as a percentage. P = patients presenting at least 1 infection over the course of a year. Percent = P over the total number of patients.

Figure 10

Survival curve of IRAK-4-deficient and MyD88-deficient patients.

Figure 11

The inflammatory phenotype of IRAK-4/MyD88-deficiency. Temperature during bacterial infection in infancy and childhood.

Figure 12

CRP concentration during bacterial infection in infancy and childhood.

Figure 13

Polymorphonuclear neutrophil counts during bacterial infection in infancy and childhood.