Critical illness from 2009 pandemic influenza A virus and bacterial coinfection in the United States.

OBJECTIVES: The contribution of bacterial coinfection to critical illness associated with 2009 influenza A virus infection remains uncertain. The objective of this study was to determine whether bacterial coinfection increased the morbidity and mortality of 2009 influenza A. DESIGN: Retrospective and prospective cohort study. SETTING: Thirty-five adult U.S. intensive care units over the course of 1 yr. PATIENTS: Six hundred eighty-three critically ill adults with confirmed or probable 2009 influenza A. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: A confirmed or probable case was defined as a positive 2009 influenza A test result or positive test for influenza A that was otherwise not subtyped. Bacterial coinfection was defined as documented bacteremia or any presumed bacterial pneumonia with or without positive respiratory tract culture within 72 hrs of intensive care unit admission. The mean age was 45±16 yrs, mean body mass index was 32.5±11.1 kg/m, and mean Acute Physiology and Chronic Health Examination II score was 21±9, with 76% having at least one comorbidity. Of 207 (30.3%) patients with bacterial coinfection on intensive care unit admission, 154 had positive cultures with Staphylococcus aureus (n=57) and Streptococcus pneumoniae (n=19), the most commonly identified pathogens. Bacterial coinfected patients were more likely to present with shock (21% vs. 10%; p=.0001), require mechanical ventilation at the time of intensive care unit admission (63% vs. 52%; p=.005), and have longer duration of intensive care unit care (median, 7 vs. 6 days; p=.05). Hospital mortality was 23%; 31% in bacterial coinfected patients and 21% in patients without coinfection (p=.002). Immunosuppression (relative risk 1.57; 95% confidence interval 1.20 -2.06; p=.0009) and Staphylococcus aureus at admission (relative risk 2.82; 95% confidence interval 1.76-4.51; p<.0001) were independently associated with increased mortality. CONCLUSIONS: Among intensive care unit patients with 2009 influenza A, bacterial coinfection diagnosed within 72 hrs of admission, especially with Staphylococcus aureus, was associated with significantly higher morbidity and mortality.

A role for PACE4 in osteoarthritis pain: evidence from human genetic association and null mutant phenotype.

OBJECTIVES: The aim of this study was to assess if genetic variation in the PACE4 (paired amino acid converting enzyme 4) gene Pcsk6 influences the risk for symptomatic knee osteoarthritis (OA). METHODS: Ten PCSK6 single nucleotide polymorphisms were tested for association in a discovery cohort of radiographic knee OA (n=156 asymptomatic and 600 symptomatic cases). Meta-analysis of the minor allele at rs900414 was performed in three additional independent cohorts (total n=674 asymptomatic and 2068 symptomatic). Pcsk6 knockout mice and wild-type C57BL/6 mice were compared in a battery of algesiometric assays, including hypersensitivity in response to intraplantar substance P, pain behaviours in response to intrathecal substance P and pain behaviour in the abdominal constriction test. RESULTS: In the discovery cohort of radiographic knee OA, an intronic single nucleotide polymorphism at rs900414 was significantly associated with symptomatic OA. Replication in three additional cohorts confirmed that the minor allele at rs900414 was consistently increased among asymptomatic compared to symptomatic radiographic knee OA cases in all four cohorts. A fixed-effects meta-analysis yielded an OR=1.35 (95% CI 1.17 to 1.56; p=4.3×10(-5) and no significant between-study heterogeneity). Studies in mice revealed that Pcsk6 knockout mice were significantly protected against pain in a battery of algesiometric assays. CONCLUSIONS: These results suggest that a variant in PCSK6 is strongly associated with protection against pain in knee OA, offering some insight as to why, in the presence of the same structural damage, some individuals develop chronic pain and others are protected. Studies in Pcsk6 null mutant mice further implicate PACE4 in pain.

The Ile585Val TRPV1 variant is involved in risk of painful knee osteoarthritis.

OBJECTIVE: To assess if a coding variant in the gene encoding transient receptor potential cation channel, subfamily V, member 1 (TRPV1) is associated with genetic risk of painful knee osteoarthritis (OA). METHODS: The Ile585Val TRPV1 variant encoded by rs8065080 was genotyped in 3270 cases of symptomatic knee OA, 1098 cases of asymptomatic knee OA and 3852 controls from seven cohorts from the UK, the USA and Australia. The genetic association between the low-pain genotype Ile-Ile and risk of symptomatic and asymptomatic knee OA was assessed. RESULTS: The TRPV1 585 Ile-Ile genotype, reported to be associated with lower thermal pain sensitivity, was associated with a lower risk of symptomatic knee OA in a comparison of symptomatic cases with healthy controls, with an odds ratio (OR) of 0.75 (95% CI 0.64 to 0.88; p=0.00039 by meta-analysis) after adjustment for age, sex and body mass index. No difference was seen between asymptomatic OA cases and controls (OR=1.02, 95% CI 0.82 to 1.27 p=0.86) but the Ile-Ile genotype was associated with lower risk of symptomatic versus asymptomatic knee OA adjusting for covariates and radiographic severity (OR=0.73, 95% CI 0.57 to 0.94 p=0.0136). TRPV1 expression in articular cartilage was increased by inflammatory cytokines (tumour necrosis factor α and interleukin 1). However, there were no differences in TRPV1 expression in healthy and arthritic synovial tissue. CONCLUSIONS: A genotype involved in lower peripheral pain sensitivity is significantly associated with a decreased risk of painful knee OA. This indicates a role for the pro-nociceptive gene TRPV1 in genetic susceptibility to symptomatic knee OA, which may also be influenced by a role for this molecule in cartilage function.

Nonsteroidal Anti-Inflammatory Drug and Aspirin Use, and Mortality among Critically Ill Pandemic H1N1 Influenza Patients: an Exploratory Analysis.

We explored nonsteroidal anti-inflammatory drug (NSAID) and aspirin (ASA) use and mortality in the U.S. Department of Health and Human Services' registry of 683 adult and 838 pediatric critically ill pandemic 2009 H1N1 influenza (pH1N1) patients. Among adults, 88 (12.9%) and 101 (14.8%) reported pre-admission use of an NSAID and ASA, respectively; mortality was similar (23-24%) regardless of NSAID or ASA use. Mortality among 89 pediatric NSAID users and 749 nonusers did not differ significantly (10.1% and 8.8%, respectively). One of 16 pediatric ASA users died. Among pediatric patients, the adjusted relative risk estimate for NSAID use and 90-day mortality was higher when influenza vaccination was included in the model (risk ratio [RR] = 1.5; 95% confidence interval, 0.7-3.2), although not statistically significant. Among adults, RR estimates did not change appreciably after adjusting for age, sex, health status, or vaccine status. We found no compelling evidence that NSAID or ASA use influenced mortality in severe pH1N1.

Role of the Nav1.7 R1150W amino acid change in susceptibility to symptomatic knee osteoarthritis and multiple regional pain.

OBJECTIVE: To assess the genetic association of pain in patients with knee osteoarthritis (OA) and those with multiple regional pain with the R1150W variant in the α-subunit of the voltage-gated sodium channel Na(V)1.7. METHODS: Knee OA patients from 2 UK cohorts (1,411 from the Genetics of Osteoarthritis and Lifestyle study and 267 from the Hertfordshire Cohort Study; 74% with symptomatic OA) with Western Ontario and McMaster Universities OA Index (WOMAC) pain scores were genotyped for rs6746030 (encoding the R1150W change). One hundred seventy-six knee OA patients (53% symptomatic) from the Clearwater Osteoarthritis Study were also tested. A total of 4,295 samples (both affected and unaffected OA) from all 3 studies with data on multiple regional pain were tested. Fixed-effects meta-analyses were carried out with the WOMAC, symptomatic OA (adjusting for radiographic severity), and multiple regional pain as outcomes. RESULTS: No association with the WOMAC was seen in the UK cohorts. Overall, the meta-analysis of WOMAC yielded a summary statistic of ß = 0.47 (95% confidence interval [95% CI] 0.04, 0.89; P = 0.030) for the variant allele. The meta-analysis of symptomatic versus asymptomatic OA did not demonstrate an association with rs6746030 (odds ratio [OR] 0.90 [95% CI 0.71, 1.15], P = 0.38). The meta-analysis of multiple regional pain resulted in a significant OR of 1.40 (95% CI 1.08, 1.80; P = 0.0085). No interstudy heterogeneity was seen for any of the analyses. CONCLUSION: We find evidence that the R1150W amino acid change in the Na(V)1.7 α-chain is associated with multiple regional pain. This variant is confirmed to be involved in genetic susceptibility to pain, but it does not appear to have a major role in OA-specific pain.