TLR4 Asp299Gly and Thr399Ile Polymorphisms: No Impact on Human Immune Responsiveness to LPS or Respiratory Syncytial Virus

A broad variety of natural environmental stimuli, genotypic influences and timing all contribute to expression of protective versus maladaptive immune responses and the resulting clinical outcomes in humans. The role of commonly co-segregating Toll-like receptor 4 (TLR4) non-synonymous single nucleotide polymorphisms Asp299Gly and Thr399Ile in this process remains highly controversial. Moreover, what differential impact these polymorphisms might have in at risk populations with respiratory dysfunction, such as current asthma or a history of infantile bronchiolitis, has never been examined. Here we determine the importance of these polymorphisms in modulating LPS and respiratory syncytial virus (RSV)--driven cytokine responses. We focus on both healthy children and those with clinically relevant respiratory dysfunction.To elucidate the impact of TLR4 Asp299Gly and Thr399Ile on cytokine production, we assessed multiple immune parameters in over 200 pediatric subjects aged 7-9. Genotyping was followed by quantification of pro- and anti-inflammatory cytokine responses by fresh peripheral blood mononuclear cells upon acute exposure to LPS or RSV.In contrast to early reports, neither SNP influenced immune responses evoked by LPS exposure or RSV infection, as measured by the intermediate phenotype of pro- and anti-inflammatory cytokine responses to these ubiquitous agents. There is no evidence of altered sensitivity in populations with "at risk" clinical phenotypes.Genomic medicine seeks to inform clinical practice. Determination of the TLR4 Asp299Gly/Thr399Ile haplotype is of no clinical benefit in predicting the nature or intensity of cytokine production in children whether currently healthy or among specific at-risk groups characterized by prior infantile broncholitis or current asthma

S. aureus colonization at ICU admission as a risk factor for developing S. aureus ICU pneumonia

OBJECTIVE: To quantify the incidence of intensive care unit (ICU) acquired pneumonia caused by Staphylococcus aureus (S. aureus) and its association with S. aureus colonization at ICU admission. METHODS: This was a post-hoc analysis of two cohort studies in critically ill patients. The primary outcome was the incidence of microbiologically confirmed S. aureus ICU-acquired pneumonia. Incidences of S. aureus ICU pneumonia and associations with S. aureus colonization at ICU admission were determined using competing risks analyses. In all ICUs, patients were screened for respiratory tract S. aureus carriage on admission as part of infection control policies. Pooling of data was deemed not possible due to heterogeneity in baseline differences in patient population. RESULTS: The two cohort studies contained data of 9,156 ICU patients. The average carriage rate of S. aureus among screened patients was 12.7%. In total, 1,185 (12.9%) patients developed ICU pneumonia. Incidences of S. aureus ICU pneumonia were 1.33% and 1.08% in cohorts 1 and 2, respectively. After accounting for competing events, the adjusted subdistribution hazard ratio (SHR) of S. aureus colonization at admission for developing S. aureus ICU pneumonia was 9.55, (95% confidence interval [CI] 5.31-17.18) in cohort 1 and 14.54 (95% CI 7.24-29.21) in cohort 2. CONCLUSION: The overall cumulative incidence of S. aureus ICU pneumonia in these ICUs was low. Patients colonized with S. aureus at ICU admission had an up to 15 times increased risk for developing this outcome compared to non-colonized patients

S. aureus colonization at ICU admission as a risk factor for developing S. aureus ICU pneumonia

OBJECTIVE: To quantify the incidence of intensive care unit (ICU) acquired pneumonia caused by Staphylococcus aureus (S. aureus) and its association with S. aureus colonization at ICU admission. METHODS: This was a post-hoc analysis of two cohort studies in critically ill patients. The primary outcome was the incidence of microbiologically confirmed S. aureus ICU-acquired pneumonia. Incidences of S. aureus ICU pneumonia and associations with S. aureus colonization at ICU admission were determined using competing risks analyses. In all ICUs, patients were screened for respiratory tract S. aureus carriage on admission as part of infection control policies. Pooling of data was deemed not possible due to heterogeneity in baseline differences in patient population. RESULTS: The two cohort studies contained data of 9,156 ICU patients. The average carriage rate of S. aureus among screened patients was 12.7%. In total, 1,185 (12.9%) patients developed ICU pneumonia. Incidences of S. aureus ICU pneumonia were 1.33% and 1.08% in cohorts 1 and 2, respectively. After accounting for competing events, the adjusted subdistribution hazard ratio (SHR) of S. aureus colonization at admission for developing S. aureus ICU pneumonia was 9.55, (95% confidence interval [CI] 5.31-17.18) in cohort 1 and 14.54 (95% CI 7.24-29.21) in cohort 2. CONCLUSION: The overall cumulative incidence of S. aureus ICU pneumonia in these ICUs was low. Patients colonized with S. aureus at ICU admission had an up to 15 times increased risk for developing this outcome compared to non-colonized patients