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 25% and 25% of patients). 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%).

Altered gene expression and possible immunodeficiency in cases of sudden infant death syndrome

“…Myd88 deficiency generally abolishes cytokine responses after TLR activation, and may therefore supress an optimal immune reaction. The mutations have been found to predispose to recurrent lifethreatening pyogenic bacterial infections, and patients with these mutations are particularly vulnerable to Pseudomonas aeruginosa, S. pneumonia, and S. aureus, especially in infancy and early childhood (12).…”

Attenuated innate immune defenses in very premature neonates during the neonatal period

“…The possibility that worse outcomes may result from a premature immune maturation of antimicrobial responses does, however, raise potential concerns of using experimental therapies aiming to "boost" immune reactivity at an earlier stage, in order to prevent neonatal infections in this age group. TLRs play a critical role in protecting against microbes in early life, as indicated by an increased vulnerability to specific bacterial and viral infections in humans with loss-of-function mutations along these molecular pathways (18). The risk of infections in these patients is greatest during the neonatal/early childhood period, underlining the importance of these receptors for immune protection during infancy (18,19).…”

“…TLRs play a critical role in protecting against microbes in early life, as indicated by an increased vulnerability to specific bacterial and viral infections in humans with loss-of-function mutations along these molecular pathways (18). The risk of infections in these patients is greatest during the neonatal/early childhood period, underlining the importance of these receptors for immune protection during infancy (18,19). As shown from previous epidemiological studies, the incidence of sepsis sharply increases in these infants shortly after birth, peaking during the first week of postnatal age, then slowly declining thereafter (20,21).…”

Inherited human IRAK-1 deficiency selectively impairs TLR signaling in fibroblasts

“…Human patients with autosomal-recessive complete IRAK-4 or MyD88 deficiency have a common clinical phenotype, characterized by extreme susceptibility to a small range of pyogenic bacterial infections, with normal resistance to other bacteria and most viruses, fungi, and parasites (41,43). IRAK-4-and MyD88-deficient patients present with meningitis, sepsis, arthritis, osteomyelitis, and deep inner-organ/tissue abscesses, mostly caused by gram-positive Streptococcus pneumoniae and S. aureus and, more rarely, by gram-negative Pseudomonas aeruginosa and Shigella sonnei .…”