MyD88 is a key downstream adapter for most Toll-like receptors (TLRs) and interleukin-1 receptors (IL-1Rs). MyD88 deficiency in mice leads to susceptibility to a broad range of pathogens in experimental settings of infection. We describe a distinct situation in a natural setting of human infection. Nine children with autosomal recessive MyD88 deficiency suffered from life-threatening, often recurrent pyogenic bacterial infections, including invasive pneumococcal disease. However, these patients were otherwise healthy, with normal resistance to other microbes. Their clinical status improved with age, but not due to any cellular leakiness in MyD88 deficiency. The MyD88-dependent TLRs and IL-1Rs are therefore essential for protective immunity to a small number of pyogenic bacteria, but redundant for host defense to most natural infections.

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. Abbreviations: CRP = C-reactive protein, ELISA = enzyme-linked immunosorbent assay, IFN = interferon, IKBA = IκBα, IL = interleukin, IL-1R = interleukin-1 receptor, InvBD = invasive bacterial disease, IRAK = interleukin-1 receptor-associated kinase, MyD = myeloid differentiation factor, NEMO = nuclear factor-kappaB essential modulator, NInvBD = noninvasive bacterial disease, TIR = Toll/IL-1R, TLR = Toll-like receptor, TNF = tumor necrosis factor.

Research from JAMA Pediatrics — Identification of Children and Adolescents at Risk for Renal Scarring After a First Urinary Tract Infection — A Meta-analysis With Individual Patient Data

The data currently available on the epidemiology, severity and economic burden of nosocomial rotavirus (RV) infections in children younger than 5 years of age in the major European countries are reviewed. In most studies, RV was found to be the major etiologic agent of pediatric nosocomial diarrhea (31-87%), although the number of diarrhea cases associated with other virus infections (eg, noroviruses, astroviruses, adenoviruses) is increasing quickly and almost equals that caused by RVs. Nosocomial RV (NRV) infections are mainly associated with infants 0-5 months of age, whereas community-acquired RV disease is more prevalent in children 6-23 months of age. NRV infections are seasonal in most countries, occurring in winter; this coincides with the winter seasonal peak of other childhood virus infections (eg, respiratory syncytial virus and influenza viruses), thus placing a heavy burden on health infrastructures. A significant proportion (20-40%) of infections are asymptomatic, which contributes to the spread of the virus and might reduce the efficiency of prevention measures given as they are implemented too late. The absence of effective surveillance and of reporting of NRV infections in any of the 6 countries studied (France, Germany, Italy, Poland, Spain and the United Kingdom) results in severe underreporting of NRV cases in hospital databases and therefore in limited awareness of the importance of NRV disease at country level. The burden reported in the medical literature is potentially significant and includes temporary reduction in the quality of children's lives, increased costs associated with the additional consumption of medical resources (increased length of hospital stay) and constraints on parents'/hospital staff's professional lives. The limited robustness and comparability of studies, together with an evolving baseline caused by national changes in health care systems, do not presently allow a complete and accurate overview of NRV disease at country level to be obtained. RV is highly contagious, and the efficiency of existing prevention measures (such as handwashing, isolation and cohorting) is variable, but low at the global level because of the existence of numerous barriers to implementation (eg, lack of staff, high staff turnover, inadequate hospital infrastructure). Prevention of RV infection by mass vaccination could have a positive impact on the incidence of NRV by reducing the number of children hospitalized for gastroenteritis, therefore reducing the number of hospital cross-infections and associated costs.

Research from JAMA Pediatrics — Serum Procalcitonin Level and Other Biological Markers to Distinguish Between Bacterial and Aseptic Meningitis in Children — A European Multicenter Case Cohort Study

We studied the distribution of peripheral B-cell subsets in patients deficient for key factors of the TLR-signaling pathways (MyD88, TIRAP/MAL, IL-1 receptor–associated kinase 4 [IRAK-4], TLR3, UNC-93B, TRIF). All TLRs, except TLR3, which signals through the TRIF adaptor, require MyD88 and IRAK-4 to mediate their function. TLR4 and the TLR2 heterodimers (with TLR1, TLR6, and possibly TLR10) require in addition the adaptor TIRAP, whereas UNC-93B is needed for the proper localization of intracellular TLR3, TLR7, TLR8, and TLR9. We found that IgM⁺IgD⁺CD27⁺ but not switched B cells were strongly reduced in MyD88-, IRAK-4-, and TIRAP-deficient patients. This defect did not appear to be compensated with age. However, somatic hypermutation of Ig genes and heavy-chain CDR3 size distribution of IgM⁺IgD⁺CD27⁺ B cells were not affected in these patients. In contrast, the numbers of IgM⁺IgD⁺CD27⁺ B cells were normal in the absence of TLR3, TRIF, and UNC-93B, suggesting that UNC-93B–dependent TLRs, and notably TLR9, are dispensable for the presence of this subset in peripheral blood. Interestingly, TLR10 was found to be expressed at greater levels in IgM⁺IgD⁺CD27⁺ compared with switched B cells in healthy patients. Hence, we propose a role for TIRAP-dependent TLRs, possibly TLR10 in particular, in the development and/or maintenance of IgM⁺IgD⁺CD27⁺ B cells in humans.