[Show abstract][Hide abstract] ABSTRACT: The advanced-age, frail elderly are especially vulnerable to developing pneumococcal infection and disease. Macrophages are critical mediators in the defence against Streptococcus pneumoniae at the upper respiratory tract, however, little is known of their anti-pneumococcal capacity in the elderly. Herein we demonstrate that monocyte-derived macrophages (MDMs) from the advanced-age, frail elderly produce less TNF, IL-6, IL-1β and IL-8 in response to heat-killed S. pneumoniae, which does not appear to be related to mRNA stability or decay. Furthermore, despite maintaining the ability to bind and phagocytose bacteria, MDMs from these individuals have a reduced capacity to kill S. pneumoniae. These defects parallel reduced PI3K-AKT signaling, which can significantly abrogate bacterial killing, but does not affect cytokine responses. Since macrophages are critical in the defence against S. pneumoniae, this study adds valuable insight into the susceptibility of the elderly to pneumococcal disease and highlights the PI3K-AKT signaling pathway as a potential therapeutic target.
[Show abstract][Hide abstract] ABSTRACT: Elevated levels of serum cytokines, a marker of immune activation and chronic inflammation, are commonly associated with age and are a significant risk factor for all-cause mortality in the elderly. This phenomenon is very similar to that exhibited by individuals with diseases of inflammatory etiology and chronic viral infections such as human immunodeficiency virus (HIV). Although the origin of chronically elevated cytokines with age is unknown, for chronic diseases and viral infections, a role for circulating bacterial products and other pattern recognition receptor (PRR) ligands has been suggested. Given this, we sought to examine whether the levels of circulating cytokines (tumour necrosis factor (TNF), interferon-gamma (IFN-γ), interleukin (IL)-1β, IL-6, IL-8, IL-10, IL-12) in the advanced-age, frail elderly (n = 135) correlated with plasma levels of lipopolysaccharide (LPS), muramyl dipeptide (MDP), 16S ribosomal DNA, total cell-free DNA and host-derived mitochondrial DNA. After adjusting for multiple testing, no associations between circulating products and donor age, sex or comorbidities were observed. However, a significant negative correlation between MDP and IL-10 was identified. Given the anti-inflammatory nature of IL-10, a negative relationship with a potent inflammatory agonist such as MDP is not surprising and suggests a potential role for circulating MDP in the propagation of age-related immune activation.
[Show abstract][Hide abstract] ABSTRACT: Infection management in advanced dementia has important implications for (1) providing high-quality care to patients near the end of life and (2) minimizing the public health threat posed by the emergence of multidrug-resistant organisms (MDROs).
JAMA Internal Medicine 08/2014; · 13.25 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Circulating myeloid cells are important mediators of the inflammatory response, acting as a major source of resident tissue antigen presenting cells and serum cytokines. They represent a number of distinct subpopulations whose functional capacity and relative concentrations are known to change with age. Little is known of these changes in the very old and physically frail, a rapidly increasing proportion of the North American population.
PLoS ONE 08/2014; 9(8):e104522. · 3.53 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We undertook a 2X2 factorial, randomized controlled trial (RCT) to assess whether vitamin D3 supplementation (10,000 international units per week) versus placebo and gargling versus no gargling could prevent viral, clinical upper respiratory tract infection (URTI) in university students.
[Show abstract][Hide abstract] ABSTRACT: Fewer Canadian seniors are vaccinated against pneumococcal disease than receive the influenza vaccine annually. Improved understanding of factors influencing pneumococcal vaccination among older adults is needed to improve vaccine uptake.
BMC Public Health 05/2014; 14(1):442. · 2.32 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To describe T-cell and natural killer (NK) cell phenotypes within nursing home elderly.
Nursing home elderly were recruited from four nursing homes in Hamilton, Ontario between September 2010 and December 2011. Healthy adults were recruited from McMaster University between September 2011 and December 2011. Nursing home elderly >=65 years were eligible; those on immunosuppressive medications were excluded. Healthy adults >=18-64 years were eligible. CD8+ and CD4+ T-cells% and their subsets, T-regs% and NK cell subset% were compared between the nursing home elderly and healthy adults.
262 nursing home elderly were enrolled; median age 87 years and 81% were female. 16 healthy adults were enrolled; median age 31 and 50% were female. There was no significant difference between CD8+ T-cell% in nursing home and healthy adults (median 17.1 versus 18.0, p = 0.56), however there were fewer naive CD8 + T-cell% (median 0.9 versus 5.2, p < 0.001), more terminally differentiated CD8 + T-cell% (median 7.3 versus 4.1, p = 0.004) and more senescent T-cell% (median 5.3 versus 3.1, p = 0.04) in the nursing home elderly. There were more CD4+ T-cell% in the nursing home elderly compared to healthy adults (median 45.5 versus 37.1, p = 0.001). Nursing home elderly had a higher CD4+/CD8+ ratio than healthy adults (2.6 versus 1.9, p = 0.048), higher T-reg% (median 1.8 versus 0.8, p < 0.001) and increased mature NK cell% (median 12.1 versus 5.4, p = 0.001) compared to healthy adults.
Differences in naive CD8+ T-cells, terminally differentiated and senescent CD8+ T-cells, T-regs and NK cell subsets were similar to studies involving community dwelling elderly. In contrast, the CD4+/CD8+ ratio was higher in nursing home elderly.
[Show abstract][Hide abstract] ABSTRACT: Lack of appropriate reporting of methodological details has previously been shown to distort risk of bias assessments in randomized controlled trials. The same might be true for observational studies. The goal of this study was to compare the Newcastle-Ottawa Scale (NOS) assessment for risk of bias between reviewers and authors of cohort studies included in a published systematic review on risk factors for severe outcomes in patients infected with influenza.
Cohort studies included in the systematic review and published between 2008-2011 were included. The corresponding or first authors completed a survey covering all NOS items. Results were compared with the NOS assessment applied by reviewers of the systematic review. Inter-rater reliability was calculated using kappa (K) statistics.
Authors of 65/182 (36%) studies completed the survey. The overall NOS score was significantly higher (p < 0.001) in the reviewers' assessment (median = 6; interquartile range [IQR] 6-6) compared with those by authors (median = 5, IQR 4-6). Inter-rater reliability by item ranged from slight (K = 0.15, 95% confidence interval [CI] = -0.19, 0.48) to poor (K = -0.06, 95% CI = -0.22, 0.10). Reliability for the overall score was poor (K = -0.004, 95% CI = -0.11, 0.11).
Differences in assessment and low agreement between reviewers and authors suggest the need to contact authors for information not published in studies when applying the NOS in systematic reviews.
BMC Medical Research Methodology 04/2014; 14(1):45. · 2.17 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Rationale: The microbial communities inhabiting the upper respiratory tract protect from respiratory infection. The maturity of the immune system is believed to be a major influence on the composition of the microbiome and, in youth, the microbiota and immune system are believed to mature in tandem. With age, immune function declines and susceptibility to respiratory infections is increases. Whether these changes contribute to the microbial composition of the respiratory tract is unknown. Objectives: Our goal was to determine whether the resident microbes of the upper respiratory tract differ between mid-aged adults (18-40 yrs) and the elderly (>65 yrs). Methods: Microbiomes of the anterior nares and oropharynx of elderly individuals were evaluated by 16S rRNA gene sequencing. These communities were compared to data on mid-aged adults obtained from the Human Microbiome Project. Measurements and Main Results: The microbiota of the elderly showed no associations with gender, co-morbidities, residence, or vaccinations. Comparisons of mid-aged adults and elderly demonstrated significant differences in the microbial composition of the anterior nares and oropharynx with age, including a population in the anterior nares of the elderly that more closely resembled the oropharynx than the anterior nares of adults. The elderly oropharyngeal microbiota were characterized by increased abundance of streptococci, specifically, Streptococcus salivarius group species, but not Streptococcus pneumoniae, carriage of which was low (<3% of participants) as demonstrated by PCR (4/123). Conclusions: The Microbial populations of the upper respiratory tract in mid-aged adults and the elderly differ; it is possible these differences contribute to the increased risk of respiratory infections experienced by the elderly.
[Show abstract][Hide abstract] ABSTRACT: Vitamin D levels are alarmingly low (<75 nmol/L) in 65-70% of North American children older than 1 year. An increased risk of viral upper respiratory tract infections (URTI), asthma-related hospitalizations and use of anti-inflammatory medication have all been linked with low vitamin D. No study has determined whether wintertime vitamin D supplementation can reduce the risk of URTI and asthma exacerbations, two of the most common and costly illnesses of early childhood. The objectives of this study are: 1) to compare the effect of 'high dose' (2000 IU/day) vs. 'standard dose' (400 IU/day) vitamin D supplementation in achieving reductions in laboratory confirmed URTI and asthma exacerbations during the winter in preschool-aged Canadian children; and 2) to assess the effect of 'high dose' vitamin D supplementation on vitamin D serum levels and specific viruses that cause URTI.Methods/design: This study is a pragmatic randomized controlled trial. Over 3 successive winters we will recruit 750 healthy children 1-5 years of age. Participating physicians are part of a primary healthcare research network called TARGet Kids! Children will be randomized to the 'standard dose' or 'high dose' oral supplemental vitamin D for a minimum of 4 months (200 children per group). Parents will obtain a nasal swab from their child with each URTI, report the number of asthma exacerbations and complete symptom checklists. Unscheduled physician visits for URTIs and asthma exacerbations will be recorded. By May, a blood sample will be drawn to determine vitamin D serum levels. The primary analysis will be a comparison of URTI rate between study groups using a Poisson regression model. Secondary analyses will compare vitamin D serum levels, asthma exacerbations and the frequency of specific viral agents between groups.
Identifying whether vitamin D supplementation of preschoolers can reduce wintertime viral URTIs and asthma exacerbations and what dose is optimal may reduce population wide morbidity and associated health care and societal costs. This information will assist in determining practice and health policy recommendations related to vitamin D supplementation in healthy Canadian preschoolers and place Canada at the forefront of pediatric vitamin D health outcomes research.
[Show abstract][Hide abstract] ABSTRACT: Vaccination is an important strategy in the prevention of influenza, but immunologic response to vaccination can vary widely. Recent studies have shown an association between serum 25-hydroxyvitamin D (25[OH]D) levels and immune function. The purpose of this study was to determine if serum 25(OH)D level correlates with influenza vaccine immunogenicity in children and adolescents.
We conducted a prospective cohort study of children age 3 to 15 years of age vaccinated with trivalent influenza vaccine (A/Brisbane/59/2007[H1N1]-like virus, A/Brisbane/10/2007 [H3N2]-like virus and B/Florida/4/2006-like virus) in Hutterite communities in Alberta, Saskatchewan and Manitoba. Serum 25(OH)D levels were measured at baseline and immunogenicity was assessed using hemagluttination inhibition (HAI) titers done at baseline and 3-5 weeks post vaccination. Logistic regression was used to assess the relationship between serum 25(OH)D level as both a continuous and dichotomous variable and seroprotection, seroconversion, fold increase in geometric mean titer (GMT) and post vaccination titer.
A total of 391 children and adolescents were included in the study and 221 (57% had post-vaccination HAI titers. The median serum 25(OH)D level was 61.0 nmol/L (Interquartile range [IQR] 50.0, 71.0). No relationship was found between serum 25(OH)D level and seroprotection (post-vaccination titer ≥40 and ≥320) or seroconversion (post-vaccination titer ≥40 for participants with pre-vaccine titer <10 or four-fold rise in post-vaccination titer for those with a pre-vaccine titer ≥10).
Serum 25(OH)D level was not associated with influenza vaccine immunogenicity in otherwise healthy children and adolescents. Other strategies to enhance influenza vaccine response should continue to be evaluated in this population. The role of serum 25(OH)D level in vaccine responsiveness in other populations, especially those hyporesponsive to influenza vaccination, requires further study.
PLoS ONE 01/2014; 9(1):e83553. · 3.53 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: BACKGROUND:A hip fracture causes bleeding, pain and immobility, and initiates inflammatory, hypercoagulable, catabolic and stress states. Accelerated surgery may improve outcomes by reducing the duration of these states and immobility. We undertook a pilot trial to determine the feasibility of a trial comparing accelerated care (i.e., rapid medical clearance and surgery) and standard care among patients with a hip fracture. METHODS:Patients aged 45 years or older who, during weekday, daytime working hours, received a diagnosis of a hip fracture requiring surgery were randomly assigned to receive accelerated or standard care. Our feasibility outcomes included the proportion of eligible patients randomly assigned, completeness of follow-up and timelines of accelerated surgery. The main clinical outcome, assessed by data collectors and adjudicators who were unaware of study group allocations, was a major perioperative complication (i.e., a composite of death, preoperative myocardial infarction, myocardial injury after noncardiac surgery, pulmonary embolism, pneumonia, stroke, and life-threatening or major bleeding) within 30 days of randomization. RESULTS:Of patients eligible for inclusion, 80% consented and were randomly assigned to groups (30 to accelerated care and 30 to standard care) at 2 centres in Canada and 1 centre in India. All patients completed 30-day follow-up. The median time from diagnosis to surgery was 6.0 hours in the accelerated care group and 24.2 hours in the standard care group (p < 0.001). A major perioperative complication occurred in 9 (30%) of the patients in the accelerated care group and 14 (47%) of the patients in the standard care group (hazard ratio 0.60, 95% confidence interval 0.26-1.39). INTERPRETATION:These results show the feasibility of a trial comparing accelerated and standard care among patients with hip fracture and support a definitive trial. Trial registration: ClinicalTrials.gov, no. NCT01344343.
Canadian Medical Association Journal 11/2013; · 5.81 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: IMPORTANCE Antibiotic-resistant bacteria are associated with increased patient morbidity and mortality. It is unknown whether wearing gloves and gowns for all patient contact in the intensive care unit (ICU) decreases acquisition of antibiotic-resistant bacteria. OBJECTIVE To assess whether wearing gloves and gowns for all patient contact in the ICU decreases acquisition of methicillin-resistant Staphylococcus aureus (MRSA) or vancomycin-resistant Enterococcus (VRE) compared with usual care. DESIGN, SETTING, AND PARTICIPANTS Cluster-randomized trial in 20 medical and surgical ICUs in 20 US hospitals from January 4, 2012, to October 4, 2012. INTERVENTIONS In the intervention ICUs, all health care workers were required to wear gloves and gowns for all patient contact and when entering any patient room. MAIN OUTCOMES AND MEASURES The primary outcome was acquisition of MRSA or VRE based on surveillance cultures collected on admission and discharge from the ICU. Secondary outcomes included individual VRE acquisition, MRSA acquisition, frequency of health care worker visits, hand hygiene compliance, health care-associated infections, and adverse events. RESULTS From the 26 180 patients included, 92 241 swabs were collected for the primary outcome. Intervention ICUs had a decrease in the primary outcome of MRSA or VRE from 21.35 acquisitions per 1000 patient-days (95% CI, 17.57 to 25.94) in the baseline period to 16.91 acquisitions per 1000 patient-days (95% CI, 14.09 to 20.28) in the study period, whereas control ICUs had a decrease in MRSA or VRE from 19.02 acquisitions per 1000 patient-days (95% CI, 14.20 to 25.49) in the baseline period to 16.29 acquisitions per 1000 patient-days (95% CI, 13.48 to 19.68) in the study period, a difference in changes that was not statistically significant (difference, -1.71 acquisitions per 1000 person-days, 95% CI, -6.15 to 2.73; P = .57). For key secondary outcomes, there was no difference in VRE acquisition with the intervention (difference, 0.89 acquisitions per 1000 person-days; 95% CI, -4.27 to 6.04, P = .70), whereas for MRSA, there were fewer acquisitions with the intervention (difference, -2.98 acquisitions per 1000 person-days; 95% CI, -5.58 to -0.38; P = .046). Universal glove and gown use also decreased health care worker room entry (4.28 vs 5.24 entries per hour, difference, -0.96; 95% CI, -1.71 to -0.21, P = .02), increased room-exit hand hygiene compliance (78.3% vs 62.9%, difference, 15.4%; 95% CI, 8.99% to 21.8%; P = .02) and had no statistically significant effect on rates of adverse events (58.7 events per 1000 patient days vs 74.4 events per 1000 patient days; difference, -15.7; 95% CI, -40.7 to 9.2, P = .24). CONCLUSIONS AND RELEVANCE The use of gloves and gowns for all patient contact compared with usual care among patients in medical and surgical ICUs did not result in a difference in the primary outcome of acquisition of MRSA or VRE. Although there was a lower risk of MRSA acquisition alone and no difference in adverse events, these secondary outcomes require replication before reaching definitive conclusions. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT0131821.
JAMA The Journal of the American Medical Association 10/2013; · 29.98 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background: Community acquired pneumonia (CAP) and invasive pneumococcal disease (IPD) are important contributors to morbidity and mortality among Canadian adults. Adult immunization with polysaccharide pneumococcal vaccines results in suboptimal disease prevention. Establishing burden of disease and healthcare utilization associated with CAP and IPD in Canada is critical to inform immunization policy for conjugate pneumococcal vaccine use in adults and to facilitate program evaluation.
Methods: The PCIRN Serious Outcomes Surveillance (SOS) Network comprises 43 adult hospitals and ~17000 beds in 7 provinces. We conducted active surveillance for CAP and IPD in 9 SOS Network sites from 12/1/10 to 12/31/12. Surveillance monitors reviewed hospitalizations daily and enrolled consenting aduts admitted with CAP or IPD. Detailed information regarding comorbidities, hospital course and outcomes were collected. Where possible, sputum and blood cultures and urine for pneumococcal urinary antigen (Binax) were collected.
Results: 2855 cases of CAP were enrolled; mean age 67.7y (17-104y); 54% were male; 37.8% >75y. 92.8% had ≥ 1 co-morbidities; 28% were immunocompromised. 31% had received pneumococcal vaccine (unknown in 35%). Mean length of stay (LOS) was 13.9d (1-738d). 10.4% developed cardiac complications, 21.4% required admission to ICU and 15.6% were ventilated. Among 1785 patients ≥ 65y, mean frail scale scores increased from 4.2 at baseline to 4.4 at 30d (p=0.02); 30d mortality was 11.1%. Overall, Spn infection was confirmed in 212 (7.4%) of patients with CAP: 133 had + blood culture, 71 had + sputum cultures, and 33 had + streptoccocal urinary antigen (UA) (311 patients had a UA performed of which 33 (11%) were positive; 29/33 of these were positive for Spn only by UA). 243 cases of IPD were enrolled. Mean age 60.2y and mean LOS was 19.8d (1-72d); 50.6% were admitted to ICU and 37% required ventilation. 30d mortality was 18.1%.
Conclusion: CAP and IPD are associated with considerable morbidity, mortality, and healthcare utilization amongst adults. Admission for CAP leads to increased frailty in older adults and assessment of burden of disease and cost-effectiveness of immunization programs should address this. Improved prevention of pneumococcal disease may result in significant cost savings.
IDWeek 2013 Meeting of the Infectious Diseases Society of America; 10/2013
[Show abstract][Hide abstract] ABSTRACT: Background: Antibiotic-resistant bacteria increase patient morbidity and mortality. It is unknown whether wearing gloves and gowns for all patient contact in the intensive care unit decreases acquisition of antibiotic-resistant bacteria.
Methods: To assess whether wearing gloves and gowns for all patient contact in the intensive care unit (ICU) decreases acquisition of methicillin-resistant Staphylococcus aureus (MRSA) or vancomycin-resistant Enterococcus (VRE) we conducted a cluster-randomized trial of 20 medical and surgical ICUs in 20 US hospitals. In the intervention arm all healthcare workers were required to wear gloves and gowns for all patient contact and when entering any patient room and compared to usual care in the control arm. The primary outcome was acquisition of MRSA or VRE based on surveillance cultures collected on admission and discharge from the ICU. Secondary outcomes included individual VRE acquisition, MRSA acquisition, frequency of healthcare-worker visits, hand hygiene compliance, healthcare-associated infections and adverse events.
Results: 26,180 patients were included and 92,241 swabs collected for the primary outcome. The primary outcome of MRSA or VRE acquisition did not significantly differ between control and intervention ICUs (20.8% vs. 14.4% relative reduction from baseline, p=0.57). For key secondary outcomes, intervention ICUs had a 40.2% relative reduction from baseline in MRSA acquisition compared with 15.0% in control ICUs (p=0.046) and no statistically significant difference in VRE acquisition (10.5% vs. 17.3% relative reduction, p=0.70). (See Figure) Universal glove and gown also decreased healthcare worker room entry (4.28 vs. 5.24 entries per hour, p=0.022), increased room exit hand hygiene compliance (78.9% vs. 62.9%, p=0.015) and had no statistically significant impact on rates of adverse event (57.1 events/1000 patient days vs. 76.4 events/1000 patient days, p=0.24).
Conclusion: Healthcare workers wearing gloves and gowns for all patient contact in the ICU setting reduced MRSA acquisition with no increase in adverse events.
Figure. Effect of universal glove and gown use on acquisition rates for VRE or MRSA.
IDWeek 2013 Meeting of the Infectious Diseases Society of America; 10/2013
[Show abstract][Hide abstract] ABSTRACT: Understanding mechanisms by which genetic variants predispose to complications of infectious diseases can lead to important benefits including the development of biomarkers to prioritize vaccination or prophylactic therapy. Family studies, candidate genes in animal models, and the absence of well-defined risks where the complications are rare all can point to genetic predisposition. The most common approach to assessing genetic risk is to conduct an association study, which is a case control study using either a candidate gene approach or a genome wide approach. Although candidate gene variants may focus on potentially causal variants, because other variants across the genome are not tested these studies frequently cannot be replicated. Genome wide association studies need a sizable sample and usually do not identify causal variants but variants which may be in linkage disequilibrium to the actual causal variant. There are many pitfalls that can lead to bias in such studies, including misclassification of cases and controls, use of improper phenotypes, and genotyping errors. These studies have been limited to common genes and rare variants may not be detected. As the use of next generation sequencing becomes more common, it can be anticipated that more variants will be confirmed. The purpose of this review article is to address the issue of genomics in infectious diseases with an emphasis on the host. Although there are a plentitude of studies that focus on the molecular characteristics of pathogens, there are far fewer studies that address the role of human genetics in the predisposition to infection or more commonly its complications. This paper will review both the approaches used to study host genetics in humans and the pitfalls associated with some of these methods. The focus will be on human disease and therefore discussion of the use of animal models will be limited to those where there are genes that have been replicated in humans. The paper will focus on common genetic variants that account for complex traits such as infectious diseases using examples from flaviviruses.
[Show abstract][Hide abstract] ABSTRACT: To determine the need of isolation precautions upon admission, we created and tested an algorithm based on a total of 474 patients with a history of carriage of an antibiotic-resistant organism. Using the algorithm upon patient admission reduced unnecessary isolations by almost 60% while maintaining a high sensitivity to predict persisting antibiotic-resistant organism colonization.
American journal of infection control 07/2013; · 3.01 Impact Factor