Serum C-Reactive Protein and Congestive Heart Failure as Significant Predictors of Herpes Zoster Vaccine Response in Elderly Nursing Home Residents.

Background: Elderly long-term care residents often exhibit a myriad of risk factors for immune dysfunction, including chronic inflammation and multiple comorbid conditions, which undoubtedly contribute to their enhanced susceptibility to infection. Hence, understanding the factors required for optimal vaccine responsiveness is critical. Methods: We examined 187 elderly nursing home residents (aged 80-102 years) and 50 community-dwelling seniors (aged 60-75 years) immunized with the live-attenuated varicella-zoster virus (VZV) vaccine. Specifically, we examined whether vaccine responsiveness was associated with serum C-reactive protein (CRP), tumor necrosis factor, interleukin 1ß, 6, and 10, leukocyte telomere length, chronic disease status, and frailty. Results: Elderly participants had significantly higher levels of CRP, tumor necrosis factor, and interleukin 6 and shorter leukocyte telomere length. Vaccine responsiveness was inversely related to the CRP level in elderly participants, but not seniors, and those with congestive heart failure were less likely to achieve a 2-fold response (odds ratio, 0.08). The latter relationship is probably due to immunosenescence, because heart failure was associated with increased senescent CD4+ T cells, and reduced naive and effector and central memory CD8+ T cells. Conclusions: In summary, these data improve our understanding of vaccine responsiveness for those in long-term care, suggesting that certain risk factors are associated with a greater likelihood of vaccine failure.

Effect of High-Dose vs Standard-Dose Wintertime Vitamin D Supplementation on Viral Upper Respiratory Tract Infections in Young Healthy Children.

IMPORTANCE: Epidemiological studies support a link between low 25-hydroxyvitamin D levels and a higher risk of viral upper respiratory tract infections. However, whether winter supplementation of vitamin D reduces the risk among children is unknown. OBJECTIVE: To determine whether high-dose vs standard-dose vitamin D supplementation reduces the incidence of wintertime upper respiratory tract infections in young children. DESIGN, SETTING, AND PARTICIPANTS: A randomized clinical trial was conducted during the winter months between September 13, 2011, and June 30, 2015, among children aged 1 through 5 years enrolled in TARGet Kids!, a multisite primary care practice-based research network in Toronto, Ontario, Canada. INTERVENTIONS: Three hundred forty-nine participants were randomized to receive 2000 IU/d of vitamin D oral supplementation (high-dose group) vs 354 participants who were randomized to receive 400 IU/d (standard-dose group) for a minimum of 4 months between September and May. MAIN OUTCOME MEASURES: The primary outcome was the number of laboratory-confirmed viral upper respiratory tract infections based on parent-collected nasal swabs over the winter months. Secondary outcomes included the number of influenza infections, noninfluenza infections, parent-reported upper respiratory tract illnesses, time to first upper respiratory tract infection, and serum 25-hydroxyvitamin D levels at study termination. RESULTS: Among 703 participants who were randomized (mean age, 2.7 years, 57.7% boys), 699 (99.4%) completed the trial. The mean number of laboratory-confirmed upper respiratory tract infections per child was 1.05 (95% CI, 0.91-1.19) for the high-dose group and 1.03 (95% CI, 0.90-1.16) for the standard-dose group, for a between-group difference of 0.02 (95% CI, -0.17 to 0.21) per child. There was no statistically significant difference in number of laboratory-confirmed infections between groups (incidence rate ratio [RR], 0.97; 95% CI, 0.80-1.16). There was also no significant difference in the median time to the first laboratory-confirmed infection: 3.95 months (95% CI, 3.02-5.95 months) for the high-dose group vs 3.29 months (95% CI, 2.66-4.14 months) for the standard-dose group, or number of parent-reported upper respiratory tract illnesses between groups (625 for high-dose vs 600 for standard-dose groups, incidence RR, 1.01; 95% CI, 0.88-1.16). At study termination, serum 25-hydroxyvitamin D levels were 48.7 ng/mL (95% CI, 46.9-50.5 ng/mL) in the high-dose group and 36.8 ng/mL (95% CI, 35.4-38.2 ng/mL) in the standard-dose group. CONCLUSIONS AND RELEVANCE: Among healthy children aged 1 to 5 years, daily administration of 2000 IU compared with 400 IU of vitamin D supplementation did not reduce overall wintertime upper respiratory tract infections. These findings do not support the routine use of high-dose vitamin D supplementation in children for the prevention of viral upper respiratory tract infections. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01419262.

Immunogenicity of Varicella Vaccine and Immunologic Predictors of Response in a Cohort of Elderly Nursing Home Residents.

BACKGROUND: Little is known about the immunogenicity of live-attenuated Oka/Merck varicella zoster virus (VZV)-containing vaccine (hereafter, "varicella vaccine") in frail nursing homes residents nor about immune phenotypes associated with a response. METHODS: A cohort of 190 frail nursing home residents aged 80-102 years and a cohort of 50 community-dwelling seniors aged 60-75 years (a comparison group) received varicella vaccine. Interferon γ (IFN-γ) enzyme-linked immunospot assays were performed before and 6 weeks after vaccination. Cellular markers of immunosenescence were measured in the nursing home elderly. RESULTS: The average number of IFN-γ spot-forming cells at baseline was significantly lower in the elderly nursing home residents than in the community-dwelling seniors. However, following vaccination, the VZV immune response increased in both cohorts, and no difference was noted in the fold difference of the response between the 2 cohorts. Upon further examination of the elderly nursing home residents, we found that higher frequencies of regulatory T cells and cytomegalovirus-specific CD4+ T cells correlated negatively with the magnitude of VZV-specific responses. CONCLUSIONS: The Oka/Merck varicella vaccine induces VZV immunity in elderly nursing home residents that is similar to that produced in community-dwelling seniors. CLINICAL TRIALS REGISTRATION: NCT01328548.

The polyfunctionality of human memory CD8+ T cells elicited by acute and chronic virus infections is not influenced by age.

As humans age, they experience a progressive loss of thymic function and a corresponding shift in the makeup of the circulating CD8+ T cell population from naïve to memory phenotype. These alterations are believed to result in impaired CD8+ T cell responses in older individuals; however, evidence that these global changes impact virus-specific CD8+ T cell immunity in the elderly is lacking. To gain further insight into the functionality of virus-specific CD8+ T cells in older individuals, we interrogated a cohort of individuals who were acutely infected with West Nile virus (WNV) and chronically infected with Epstein Barr virus (EBV) and Cytomegalovirus (CMV). The cohort was stratified into young (<40 yrs), middle-aged (41-59 yrs) and aged (>60 yrs) groups. In the aged cohort, the CD8+ T cell compartment displayed a marked reduction in the frequency of naïve CD8+ T cells and increased frequencies of CD8+ T cells that expressed CD57 and lacked CD28, as previously described. However, we did not observe an influence of age on either the frequency of virus-specific CD8+ T cells within the circulating pool nor their functionality (based on the production of IFNγ, TNFα, IL2, Granzyme B, Perforin and mobilization of CD107a). We did note that CD8+ T cells specific for WNV, CMV or EBV displayed distinct functional profiles, but these differences were unrelated to age. Collectively, these data fail to support the hypothesis that immunosenescence leads to defective CD8+ T cell immunity and suggest that it should be possible to develop CD8+ T cell vaccines to protect aged individuals from infections with novel emerging viruses.

DO IT Trial: vitamin D Outcomes and Interventions in Toddlers - a TARGet Kids! randomized controlled trial.

BACKGROUND: 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 4 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. DISCUSSION: 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.

Effects of school closure on incidence of pandemic influenza in Alberta, Canada.

BACKGROUND: Control of pandemic influenza by social-distancing measures, such as school closures, is a controversial aspect of pandemic planning. However, investigations of the extent to which these measures actually affect the progression of a pandemic have been limited. OBJECTIVE: To examine correlations between the incidence of pandemic H1N1 (pH1N1) influenza in Alberta, Canada, in 2009 and school closures or weather changes, and to estimate the effects of school closures and weather changes on pH1N1 transmission. DESIGN: Mathematical transmission models were fit to data that compared the pattern of confirmed pH1N1 cases with the school calendar and weather patterns. SETTING: Alberta, Canada, from 19 April 2009 to 2 January 2010. DATA SOURCES: 2009 virologic test results, 2006 census data, 2009 daily temperature and humidity data, and 2009 school calendars. MEASUREMENTS: Age-specific daily counts of positive results for pH1N1 from the complete database of 35 510 specimens submitted to the Alberta Provincial Laboratory for Public Health for virologic testing from 19 April 2009 to 2 January 2010. RESULTS: The ending and restarting of school terms had a major effect in attenuating the first wave and starting the second wave of pandemic influenza cases. Mathematical models suggested that school closure reduced transmission among school-age children by more than 50% and that this was a key factor in interrupting transmission. The models also indicated that seasonal changes in weather had a significant effect on the temporal pattern of the epidemic. LIMITATIONS: Data probably represent a small sample of all viral infections. The mathematical models make simplifying assumptions in order to make simulations and analysis feasible. CONCLUSION: Analysis of data from unrestricted virologic testing during an influenza pandemic provides compelling evidence that closing schools can have dramatic effects on transmission of pandemic influenza. School closure seems to be an effective strategy for slowing the spread of pandemic influenza in countries with social contact networks similar to those in Canada. PRIMARY FUNDING SOURCE: Canadian Institutes of Health Research, Natural Sciences and Engineering Research Council of Canada, and Public Health Agency of Canada.

The memory T cell response to West Nile virus in symptomatic humans following natural infection is not influenced by age and is dominated by a restricted set of CD8+ T cell epitopes.

We examined the West Nile virus (WNV)-specific T cell response in a cohort of 52 patients with symptomatic WNV infections, including neuroinvasive and non-invasive disease. Although all virus proteins were shown to contain T cell epitopes, certain proteins, such as E, were more commonly targeted by the T cell response. Most patients exhibited reactivity toward 3-4 individual WNV peptides; however, several patients exhibited reactivity toward >10 individual peptides. The relative hierarchy of T cell reactivities in all patients showed a fixed pattern that was sustained throughout the 12-mo period of the current study. Surprisingly, we did not observe any relationship between age and either the breadth or magnitude of the T cell response following infection. We also did not observe a relationship between disease severity and either the breadth or magnitude of the T cell response. The T cell epitopes were distributed in a non-random fashion across the viral polyprotein and a limited number of epitopes appeared to dominate the CD8(+) T cell response within our cohort. These data provide important new insight into the T cell response against WNV in humans.

Deciphering epitope specificities within polyserum using affinity selection of random peptides and a novel algorithm based on pattern recognition theory.

While numerous strategies have been developed to map epitope specificities for monoclonal antibodies, few have been designed for elucidating epitope specificity within complex polysera. We have developed a novel algorithm based on pattern recognition theory that can be used to characterize the breadth of epitope specificities within a polyserum based on affinity selection of random peptides. To attribute these random peptides to a specific epitope, the sequences of the affinity-selected peptides were matched against a database of random peptides selected using well-described monoclonal antibodies. To test this novel algorithm, we employed polyserum from patients infected with West Nile virus and isolated 109 unique sequences which were recognized selectively by serum from West Nile virus-infected patients but not uninfected patients. Through application of our algorithm, it was possible to match 20% of the polyserum-selected peptides to the database of peptides isolated by affinity selection using monoclonal antibodies against the virus envelope protein. Statistical analysis demonstrated that the peptides selected with the polyserum could not be attributed to the peptide database by chance. This novel algorithm provides the basis for further development of methods to characterize the breadth of epitope recognition within a complex pool of antibodies.

A novel computer algorithm improves antibody epitope prediction using affinity-selected mimotopes: a case study using monoclonal antibodies against the West Nile virus E protein.

Understanding antibody function is often enhanced by knowledge of the specific binding epitope. Here, we describe a computer algorithm that permits epitope prediction based on a collection of random peptide epitopes (mimotopes) isolated by antibody affinity purification. We applied this methodology to the prediction of epitopes for five monoclonal antibodies against the West Nile virus (WNV) E protein, two of which exhibit therapeutic activity in vivo. This strategy was validated by comparison of our results with existing F(ab)-E protein crystal structures and mutational analysis by yeast surface display. We demonstrate that by combining the results of the mimotope method with our data from mutational analysis, epitopes could be predicted with greater certainty. The two methods displayed great complementarity as the mutational analysis facilitated epitope prediction when the results with the mimotope method were equivocal and the mimotope method revealed a broader number of residues within the epitope than the mutational analysis. Our results demonstrate that the combination of these two prediction strategies provides a robust platform for epitope characterization.

Effect of High-Dose Vitamin D Supplementation on Upper Respiratory Tract Infection Symptom Severity in Healthy Children.

BACKGROUND: Observational studies support the role of vitamin D in reducing viral upper respiratory tract infection (URTI) symptom severity in adults and children. This study assessed whether wintertime high-dose vitamin D supplementation (2000 IU/day) reduces URTI symptom severity compared with standard-dose (400 IU/day) supplementation in preschool children. Secondary objectives were to assess effects of high-dose supplementation on outpatient physician visits, emergency department (ED) visits and antibiotic prescriptions for URTI. METHODS: This was a secondary analysis of a multisite randomized clinical trial involving 703 healthy 1- to 5-year-old children in Toronto, Canada. High-dose or standard-dose oral vitamin D was randomly assigned for 1 winter season. For each URTI, parents completed symptom checklists based on the Canadian Acute Respiratory and Flu Scale. Symptom severity, frequency of outpatient visits, ED visits and antibiotic prescriptions for URTI between groups were analyzed using negative binomial regression. RESULTS: URTI symptom severity was not reduced in the high-dose vs. standard-dose group [incidence rate ratio (IRR) = 0.97; 95% confidence interval (CI): 0.76-1.23]. High-dose vitamin D did not decrease frequency of outpatient visits (IRR = 1.16; 95% CI: 0.84-1.60), ED visits (IRR = 1.17; 95% CI: 0.57-2.40) or antibiotic prescriptions (IRR=1.02; 95% CI: 0.61-1.72). Serum 25-hydroxyvitamin D was higher in the high-dose group (48.7 ng/mL; 95% CI: 46.9-50.5) than the standard-dose group (36.8 ng/mL; 95% CI: 35.4-38.2; P < 0.001). CONCLUSIONS: High-dose vitamin D supplementation did not reduce URTI symptom severity, outpatient visits, ED visits or antibiotic prescriptions relative to standard-dose. These results do not support vitamin D supplementation above the standard recommended dose for reducing URTI symptoms in children.

Comparing estimates of influenza-associated hospitalization and death among adults with congestive heart failure based on how influenza season is defined.

BACKGROUND: There is little consensus about how the influenza season should be defined in studies that assess influenza-attributable risk. The objective of this study was to compare estimates of influenza-associated risk in a defined clinical population using four different methods of defining the influenza season. METHODS: Using the Studies of Left Ventricular Dysfunction (SOLVD) clinical database and national influenza surveillance data from 1986-87 to 1990-91, four definitions were used to assess influenza-associated risk: (a) three-week moving average of positive influenza isolates is at least 5%, (b) three-week moving average of positive influenza isolates is at least 10%, (c) first and last positive influenza isolate are identified, and (d) 5% of total number of positive isolates for the season are obtained. The clinical data were from adults aged 21 to 80 with physician-diagnosed congestive heart failure. All-cause hospitalization and all-cause mortality during the influenza seasons and non-influenza seasons were compared using four definitions of the influenza season. Incidence analyses and Cox regression were used to assess the effect of exposure to influenza season on all-cause hospitalization and death using all four definitions. RESULTS: There was a higher risk of hospitalization associated with the influenza season, regardless of how the start and stop of the influenza season was defined. The adjusted risk of hospitalization was 8 to 10 percent higher during the influenza season compared to the non-influenza season when the different definitions were used. However, exposure to influenza was not consistently associated with higher risk of death when all definitions were used. When the 5% moving average and first/last positive isolate definitions were used, exposure to influenza was associated with a higher risk of death compared to non-exposure in this clinical population (adjusted hazard ratios [HR], 1.16; 95% confidence interval [CI], 1.04 to 1.29 and adjusted HR, 1.19; 95% CI, 1.06 to 1.33, respectively). CONCLUSION: Estimates of influenza-attributable risk may vary depending on how influenza season is defined and the outcome being assessed.

DNA methylation patterns are related to co-morbidity status and circulating C-reactive protein levels in the nursing home elderly.

Elderly residents of long-term care commonly exhibit a number of age-related health deficits, including impaired physical and cognitive function, chronic illnesses, and chronic inflammation. Given our previous data relating the phenotype and function of innate and adaptive leukocytes from the nursing home elderly to chronic conditions and inflammatory biomarkers, we hypothesized that these factors would influence the regulatory programming of immune cells, thereby contributing to immune dysfunction. Since DNA methylation represents both an important regulatory mechanism of cells as well as a biomarker of health and disease, we sought to characterize the methylome of peripheral blood mononuclear cells (PBMCs) from the nursing home elderly (n=23; 82-98years old, 70% female), and compare these patterns to pathological factors such as dementia, co-morbidity score and frailty, and immune-related factors such as serum C-reactive protein (CRP) and cytokine levels and varicella-zoster virus (VZV) vaccine responsiveness. We show that the most significant changes in DNA methylation levels occurred in relation to co-morbidity score, including one site, cg07725579 (FDR-adjusted p<0.05; closest gene, SIRBP2), and nine DNA methylation regions (Stouffer's p<0.05). DNA methylation age, although not strongly correlated with chronological age, was positively correlated with serum CRP levels (p=0.007), and negatively correlated with vaccine responsiveness (p=0.035). To our knowledge, this study is one of the first to describe associations of DNA methylation patterns with pathological and immune-related factors in residents of long-term care, and may provide important clues pertaining to immune cell dysfunction near the end of life.

Pneumonia and lower respiratory infections in nursing home residents: predictors of hospitalization and mortality.

OBJECTIVES: To compare predictors of hospitalization and death in nursing home residents with pneumonia and other lower respiratory infections (LRIs). DESIGN: A nested cohort study. SETTING: Nine nursing homes in southern Ontario. PARTICIPANTS: Three hundred fifty-three nursing home residents with LRIs (enrolled in the control arm of a clinical trial). MEASUREMENTS: Comorbidities, vaccination status, age, health-related quality of life, functional status, and vital statistics were evaluated as potential predictors of hospitalization and mortality at 30 days. RESULTS: Moderate to high disease severity score on a practical severity scale was a strong independent predictor of hospitalization (odds ratio (OR)=7.12, P<.001) and mortality (OR=5.04, P=.003). Diagnosis of pneumonia, established using chest radiograph, was also associated with hospitalization (OR=2.43, P=.008) and mortality (OR=2.35, P=.02). Oxygen saturation (<90%) was a strong independent predictor of hospitalization (OR=3.02, P=.004) but was not a significant predictor of mortality in multivariable analyses. Diagnosis of congestive heart failure (OR=2.26, P=.02) was an independent predictor of hospitalization, whereas receipt of pneumococcal vaccine (OR=0.36, P=.01) and greater functional independence (OR=0.92, P=.02) were negatively associated with hospitalization. CONCLUSION: In nursing home residents with LRI, severity of illness and radiographically confirmed pneumonia are predictive of death and hospitalization.

Interobserver reliability of radiologists' interpretations of mobile chest radiographs for nursing home-acquired pneumonia.

OBJECTIVES: To determine the interobserver reliability of radiologists' interpretations of mobile chest radiographs for nursing home-acquired pneumonia. DESIGN: A cross-sectional reliability study. SETTING: Nursing homes and an acute care hospital. PARTICIPANTS: Four radiologists reviewed 40 mobile chest radiographs obtained from residents of nursing homes who met a clinical definition of lower respiratory tract infections. MEASUREMENTS: Radiologists were asked to interpret radiographs with respect to the film quality; presence, pattern, and extent of an infiltrate; and the presence of a pleural effusion or adenopathy. Interrater reliability was evaluated using the intraclass correlation coefficient derived from a 2-way random effects model. RESULTS: On average the radiologists reported that 6 of the 40 films were of very good or excellent quality and 16 of the 40 were of fair or poor quality. When the finding of an infiltrate was dichotomized (0 = no; 1 = possible, probable, or definite) all 4 radiologists agreed on 21 of the 37 chest radiographs. The intraclass correlation coefficient for the presence or absence of infiltrates was 0.54 (95% confidence intervals [CI] 0.38 to 0.69). For the 14 radiographs where infiltrates were observed by all radiologists, intraclass correlation coefficients for the presence of pleural effusions was 0.08 (95% CI -0.10 to 0.41), hilar adenopathy 0.54 (95% CI 0.29 to 0.79), and mediastinal adenopathy 0.49 (95% CI 0.21 to 0.76). CONCLUSION: In conclusion, the interrater agreement among radiologists for mobile chest radiographs in establishing the presence or absence of an infiltrate can be judged to be "fair." Treatment decisions need to include clinical findings and should not be made based on radiographic findings alone.

Use of a broader determinants of health model for community-acquired pneumonia in seniors.

Community-acquired pneumonia in older adults represents an important clinical and public health challenge. This article discusses the role that factors such as socioeconomic status, air pollution, crowding, exposure to tobacco smoke, and nutrition play in predisposing elderly persons to such respiratory infections. It is proposed that a model that addresses these factors is needed for a comprehensive understanding of these infections. Although the causal pathways may be unclear, there are data to suggest a relationship between low socioeconomic status and risk of acquiring respiratory infection. The need for more research in this area is emphasized.

Community-acquired pneumonia in older people: the need for a broader perspective.

Community-acquired pneumonia (CAP) poses a substantial threat to the health of older adults. The incidence of this infection and mortality associated with it increase with age. Despite the considerable effect of CAP on older adults, little is known about the effect of socioeconomic and environmental factors on CAP in older people. This paper argues that broader determinants, including socioeconomic status (SES), nutrition, and factors in the physical environment such as exposure to tobacco smoke and air pollution need to be evaluated as potential risk factors for CAP in older adults. Data suggesting a relationship between low SES and risk of acquiring CAP exist; possible causal pathways include increased exposure through crowding or increased susceptibility to infection. Inadequate nutrition, exposure to tobacco smoke, air pollution, and not receiving immunization may predispose older people to lower respiratory tract infection. This study reviews current evidence for these potential risk factors and suggests priorities for research. A thorough understanding of these factors and their underlying biological mechanisms is needed to develop successful health-promotion strategies such as better immunization strategies and educational programs about nutrition. Determining the effect of air pollution on CAP in older adults is important in terms of reducing personal risk to older individuals and for healthcare agencies charged with formulating policy to protect the health of older adults.

Interventions to prevent aspiration pneumonia in older adults: a systematic review.

A systematic review was conducted to assess the effectiveness of the following interventions for prevention of aspiration pneumonia (AP) in older adults: compensatory strategy/positioning changes, dietary interventions, pharmacologic therapies, oral hygiene, and tube feeding. Data sources included a key word search of the MEDLINE, EMBASE, Cochrane Library, CINAHL, and HealthSTAR databases and hand searches of six journals. Reference lists of relevant primary and review articles were searched. Studies included were randomized, controlled trials (RCTs) enrolling adults aged 65 and older at risk of and assessed for AP. Two investigators extracted data on population, intervention, outcomes, and methodological quality. Of the 17 identified RCTs, eight met the selection criteria, two addressed dietary management or compensatory swallowing, two assessed pharmacological therapies, one assessed oral hygiene, and three assessed tube feeding. None of the eight trials reported use of blinding, and allocation concealment was unclear in five. Use of amantadine prevented pneumonia in one trial of nursing home residents. The antithrombotic agent cilostazol prevented AP in another trial but resulted in excessive bleeding. Insufficient data exist to determine the effectiveness of positioning strategies, modified diets, oral hygiene, feeding tube placement, or delivery of food in preventing AP. Considering how common the problem of AP is in older adults, larger, high-quality RCTs on the effectiveness of preventive interventions are warranted.

A randomized, controlled trial of doxycycline and rifampin for patients with Alzheimer's disease.

OBJECTIVES: To assess whether doxycycline and rifampin have a therapeutic role in patients with Alzheimer's disease (AD). DESIGN: Randomized, triple-blind, controlled trial. SETTING: Three tertiary care and two community geriatric clinics in Canada. PARTICIPANTS: One hundred one patients with probable AD and mild to moderate dementia. INTERVENTION: Oral daily doses of doxycycline 200 mg and rifampin 300 mg for 3 months. MEASUREMENTS: The primary outcome was a change in Standardized Alzheimer's Disease Assessment Scale cognitive subscale (SADAScog) at 6 months. Secondary outcomes were changes in the SADAScog at 12 months and tests of dysfunctional behavior, depression, and functional status. RESULTS: There was significantly less decline in the SADAScog score at 6 months in the antibiotic group than in the placebo group, (-2.75 points, 95% confidence interval (CI)=-5.28 to -0.22, P=.034). At 12 months, the difference between groups in the SADAScog was -4.31 points (95% CI=-9.17-0.56, P=.079). The antibiotic group showed significantly less dysfunctional behavior at 3 months. There was no significant difference in adverse events between groups (P=.34). There were no differences in Chlamydia pneumoniae detection using polymerase chain reaction or antibodies (immunoglobulin (Ig)G or IgA) between groups. CONCLUSION: Therapy with doxycycline and rifampin may have a therapeutic role in patients with mild to moderate AD. The mechanism is unlikely to be due to their effect on C. pneumoniae. More research is needed to investigate these agents.

Nursing home-acquired pneumonia: an emergency department treatment algorithm.

Nursing home-acquired pneumonia (NHAP) is a leading cause of morbidity, hospitalization, and mortality among older nursing home residents. Too often, these patients are erroneously grouped with cases of community-acquired and hospital-acquired pneumonia. Yet, they differ in terms of most common pathogens, significant underlying disease, impaired functional and cognitive status, and poor nutrition. The NHAP emergency department treatment algorithm presented here shows that an important decision for initial care in the emergency department (ED) is whether the patient should return to the nursing home. This decision often is based on the facility's ability to administer parenteral antibiotics, and care for co-morbidities and complications. Cephalosporins are the foundation of initial treatment of NHAP in the ED, and are combined with other antibiotics in anticipation of the most likely pathogens and treatment variables discussed here. It is hoped the NHAP treatment algorithm will contribute to improved outcomes.

Antimicrobial drugs for treating methicillin-resistant Staphylococcus aureus colonization.

BACKGROUND: Eradication strategies for methicillin-resistant Staphylococcus aureus (MRSA) are variable. We sought to summarize the evidence for use of antimicrobial agents to eradicate MRSA. OBJECTIVES: To describe the effects of topical and systemic antimicrobial agents on nasal and extra-nasal MRSA carriage, adverse events, and incidence of subsequent MRSA infections. SEARCH STRATEGY: We searched the Cochrane Infectious Diseases Group's trials register (August 2003), the Cochrane Central Register of Controlled Trials (Issue 3, 2003), MEDLINE (1966 to 2003), EMBASE (1988 to 2003), handsearched relevant literature, and contacted MRSA experts and the manufacturer of mupirocin. SELECTION CRITERIA: Randomized controlled trials of patients colonized with MRSA comparing topical or systemic antimicrobials to placebo or no treatment, and trials comparing various combinations of topical or systemic agents to no treatment, placebo, or to topical or systemic agents. DATA COLLECTION AND ANALYSIS: Two reviewers independently applied inclusion criteria to potentially relevant trials, assessed trial methodological quality, and extracted data. Primary outcomes included eradication of MRSA, infection due to MRSA, and adverse events. MAIN RESULTS: Six trials (384 participants) met the inclusion criteria. No difference in MRSA eradication was detected in four studies: one that compared mupirocin to placebo, two that compared one systemic agent to no treatment (fusidic acid in one and rifampin or minocycline in the other) and one that compared mupirocin to topical fusidic acid and oral trimethoprim-sulfamethoxazole, examining nasal MRSA eradication as an outcome. One study compared minocycline to rifampin, with rifampicin being more effective in relation to eradication of MRSA from all sites at day 30 (relative risk 0.16; 95% confidence intervals 0.02 to 1.00), but the difference at 90 days was not statistically significant (n = 18). Two studies (one testing novobiocin and rifampin, the other ciprofloxacin and rifampin, versus trimethoprim-sulfamethoxazole and rifampin) did not demonstrate a difference in eradication of MRSA at all sites (n = 94). Adverse events with systemic agents occurred in up to 20% of participants, however reporting was sporadic and denominators small. All trials reported development of resistance to antimicrobial agents used. REVIEWER'S CONCLUSIONS: There is insufficient evidence to support use of topical or systemic antimicrobial therapy for eradicating nasal or extra-nasal MRSA. There is no demonstrated superiority of either topical or systemic therapy, or of combinations of these agents. Potentially serious adverse events and development of antimicrobial resistance can result from therapy.