Identifying research priorities on infections in older adults:Proceedings of an interdisciplinary workshop

Background: Infections pose a substantial burden to the health of older adults. In this report, we describe the proceedings of a workshop to formulate and prioritize research questions about infections in older adults using an interdisciplinary approach. Methods: Researchers from four sectors (basic science, clinical sciences, health services and epidemiology/determinants of health) and representatives from various Canadian local, provincial, and federal stakeholder groups were invited to a two-day workshop. Five multi-disciplinary groups and stakeholders from each of three healthcare settings (long term, acute care and community) discussed research priorities for each of the settings. Five to ten research questions were identified for each setting. Results: The research questions proposed ranged from risk factors and outcomes for different infections to the effect of nutrition on infection and the role of alternative and complementary medicine in treating infections. Health service issues included barriers to immunization, prolongation of hospital length of stay by infection, use of care paths for managing infections, and decision-making in determining the site of care for individuals with infections. Clinical questions included risk factor assessment for infection, the effectiveness of preventative strategies, and technology evaluation. Epidemiologic issues included the challenge of achieving a better understanding of respiratory infections in the community and determining the prevalence of colonization with multi-resistant bacteria. Conclusions: The questions are of direct relevance to researchers in a wide variety of fields. Bringing together a multi-disciplinary group of researchers to frame and prioritize research questions about aging is feasible, participants valued the opinions of people working in other areas.

Effect of a multifaceted intervention on number of antimicrobial prescriptions for suspected urinary tract infections in residents of nursing homes:Cluster randomised controlled trial

Objective: To assess whether a multifaceted intervention can reduce the number of prescriptions for antimicrobials for suspected urinary tract infections in residents of nursing homes. Design: Cluster randomised controlled trial. Setting: 24 nursing homes in Ontario, Canada, and Idaho, United States. Participants: 12 nursing homes allocated to a multifaceted intervention and 12 allocated to usual care. Outcomes were measured in 4217 residents. Interventions: Diagnostic and treatment algorithm for urinary tract infections implemented at the nursing home level using a multifaceted approach-small group interactive sessions for nurses, videotapes, written material, outreach visits, and one on one interviews with physicians. Main outcome measures: Number of antimicrobials prescribed for suspected urinary tract infections, total use of antimicrobials, admissions to hospital, and deaths. Results: Fewer courses of antimicrobials for suspected urinary tract infections per 1000 resident days were prescribed in the intervention nursing homes than in the usual care homes (1.17 v 1.59 courses; weighted mean difference -0.49, 95% confidence intervals -0.93 to -0.06). Antimicrobials for suspected urinary tract infection represented 28.4% of all courses of drugs prescribed in the intervention nursing homes compared with 38.6% prescribed in the usual care homes (weighted mean difference -9.6%, -16.9% to -2.4%). The difference in total antimicrobial use per 1000 resident days between intervention and usual care groups was not significantly different (3.52 v 3.93; weighed mean difference -0.37, -1.17 to 0.44). No significant difference was found in admissions to hospital or mortality between the study arms. Conclusion: A multifaceted intervention using algorithms can reduce the number of antimicrobial prescriptions for suspected urinary tract infections in residents of nursing homes.

Evidence-Based Clinical Pathways To Manage Urinary Tract Infections in Long-Term Care Facilities:A Qualitative Case Study Describing Administrator and Nursing Staff Views

Objectives: This article examines the views of nursing staff and administrators in long-term care facilities (LTCFs) regarding a clinical pathway for managing urinary tract infections (UTIs) in LTCF residents. Design: A qualitative (case study) design was used. Setting: Data were collected from 8 LTCFs in southern Ontario and 2 in Iowa enrolled in a larger randomized controlled trial of clinical pathway for managing UTIs in LTCF residents, conducted between September 2001 and March 2003. The clinical pathway, designed to more effectively identify, diagnose, and treat UTIs, and reduce inappropriate antibiotics use for asymptomatic UTIs, introduced 2 decision tools to determine when to order a urine culture and initiate antibiotic treatment for suspected UTIs. Participants: We conducted 19 individual interviews with administrators and 10 focus groups with 52 nurses. Findings: Nurses generally thought that the pathways were well developed and easy to use, and administrators believed they were an important educational resource. Barriers to their use varied by group-initial lack of buy-in from nurses (medical directors), additional work (directors of nursing), and the need to change the protocol to exclude certain residents based on prior health conditions and/or pressure from physicians or families (nurses). Conclusions: Both administrators and staff, once familiar with a new clinical protocol to improve UTI management in LTCFs, generally supported its use. © 2007 American Medical Directors Association.

Community-acquired infections and their association with myeloid malignancies

Introduction: Antigenic stimulation is a proposed aetiologic mechanism for many haematological malignancies. Limited evidence suggests that community-acquired infections may increase the risk of acute myeloid leukaemia (AML) and myelodysplastic syndrome (MDS). However, associations with other myeloid malignancies including chronic myeloid leukaemia (CML) and myeloproliferative neoplasms (MPNs) are unknown.

Materials and methods: Using the Surveillance, Epidemiology and End Result (SEER)-Medicare database, fourteen community-acquired infections were compared between myeloid malignancy patients [AML (n=8489), CML (n=3626) diagnosed 1992-2005; MDS (n=3072) and MPNs (n=2001) diagnosed 2001-2005; and controls (200,000 for AML/CML and 97,681 for MDS/MPN]. Odds ratios (ORs) and 95% confidence intervals were adjusted for gender, age and year of selection excluding infections diagnosed in the 13-month period prior to selection to reduce reverse causality.

Results: Risk of AML and MDS respectively, were significantly associated with respiratory tract infections, bronchitis (ORs 1.20 [95% CI: 1.14-1.26], 1.25 [95% CI: 1.16-1.36]), influenza (ORs 1.16 [95% CI: 1.07-1.25], 1.29 [95% CI: 1.16-1.44]), pharyngitis (ORs 1.13 [95% CI: 1.06-1.21], 1.22 [95% CI: 1.11-1.35]), pneumonia (ORs 1.28 [95% CI: 1.21-1.36], 1.52 [95% CI: 1.40-1.66]), sinusitis (ORs 1.23 [95% CI: 1.16-1.30], 1.25 [95% CI: 1.15-1.36]) as was cystitis (ORs 1.13 [95% CI: 1.07-1.18], 1.26 [95% CI: 1.17-1.36]). Cellulitis (OR 1.51 [95% CI: 1.39-1.64]), herpes zoster (OR 1.31 [95% CI: 1.14-1.50]) and gastroenteritis (OR 1.38 [95% CI: 1.17-1.64]) were more common in MDS patients than controls. For CML, associations were limited to bronchitis (OR 1.21 [95% CI: 1.12-1.31]), pneumonia (OR 1.49 [95% CI: 1.37-1.62]), sinusitis (OR 1.19 [95% CI: 1.09-1.29]) and cellulitis (OR 1.43 [95% CI: 1.32-1.55]) following Bonferroni correction. Only cellulitis (OR 1.34 [95% CI: 1.21-1.49]) remained significant in MPN patients. Many infections remained elevated when more than 6 years of preceding claims data were excluded.

Discussion: Common community-acquired infections may be important in the malignant transformation of the myeloid lineage. Differences in the aetiology of classic MPNs and other myeloid malignancies require further exploration.

Lactobacillus strains isolated from infant faeces possess potent inhibitory activity against intestinal alpha- and beta-glucosidases suggesting anti-diabetic potential

Purpose: Inhibitors of intestinal alpha-glucosidases are used therapeutically to treat type 2 diabetes mellitus. Bacteria such as Actinoplanes sp. naturally produce potent alpha-glucosidase inhibitor compounds, including the most widely available drug acarbose. It is not known whether lactic acid bacteria (LAB) colonising the human gut possess inhibitory potential against glucosidases. Hence, the study was undertaken to screen LABs having inherent alpha- and beta-glucosidase inhibitory potential. Methods: This study isolated, screened, identified and extracted Lactobacillus strains (Lb1–15) from human infant faecal samples determining their inhibitory activity against intestinal maltase, sucrase, lactase and amylase. Lactobacillus reference strains (Ref1–7), a Gram positive control (Ctrl1) and two Gram negative controls (Ctrl2–3), were also analysed to compare activity. Results: Faecal isolates were identified by DNA sequencing, with the majority identified as unique strains of Lactobacillus plantarum. Some strains (L. plantarum, L. fermentum, L. casei and L. rhamnosus) had potent and broad spectrum inhibitory activities (up to 89 %; p < 0.001; 500 mg/ml wet weight) comparable to acarbose (up to 88 %; p < 0.001; 30 mg/ml). Inhibitory activity was concentration-dependent and was freely available in the supernatant, and was not present in other bacterial genera (Bifidobacterium bifidum and Escherichia coli or Salmonella typhimurium). Interestingly, the potency and spectrum of inhibitory activity across strains of a single species (L. plantarum) differed substantially. Some Lactobacillus extracts had broader spectrum activities than acarbose, effectively inhibiting beta-glucosidase activity (lactase) as well as alpha-glucosidase activities (maltase, sucrase and amylase). Anti-diabetic potential was indicated by the fact that oral gavage with a L. rhamnosus extract (1 g/kg) was able to reduce glucose excursions (Area under curve; 22 %; p < 0.05) in rats during a carbohydrate challenge (starch; 2 g/kg). Conclusion: These results definitively demonstrate that Lactobacillus strains present in the human gut have alpha- and beta-glucosidase inhibitory activities and can reduce blood glucose responses in vivo. Although the potential use of LAB such as Lactobacillus as a dietary supplement, medicinal food or biotherapeutic for diabetes is uncertain, such an approach might offer advantages over drug therapies in terms of broader spectrum activities and fewer unpleasant side effects. Further characterisation of this bioactivity is warranted, and chronic studies should be undertaken in appropriate animal models or diabetic subjects.

Respiratory syncytial virus infections enhance cigarette smoke induced COPD in mice

Respiratory syncytial viral (RSV) infections are a frequent cause of chronic obstructive pulmonary disease (COPD) exacerbations, which are a major factor in disease progression and mortality. RSV is able to evade antiviral defenses to persist in the lungs of COPD patients. Though RSV infection has been identified in COPD, its contribution to cigarette smoke-induced airway inflammation and lung tissue destruction has not been established. Here we examine the long-term effects of cigarette smoke exposure, in combination with monthly RSV infections, on pulmonary inflammation, protease production and remodeling in mice. RSV exposures enhanced the influx of macrophages, neutrophils and lymphocytes to the airways of cigarette smoke exposed C57BL/6J mice. This infiltration of cells was most pronounced around the vasculature and bronchial airways. By itself, RSV caused significant airspace enlargement and fibrosis in mice and these effects were accentuated with concomitant smoke exposure. Combined stimulation with both smoke and RSV synergistically induced cytokine (IL-1a, IL-17, IFN-c, KC, IL-13, CXCL9, RANTES, MIF and GM-CSF) and protease (MMP-2, -8, -12, -13, -16 and cathepsins E, S, W and Z) expression. In addition, RSV exposure caused marked apoptosis within the airways of infected mice, which was augmented by cigarette smoke exposure. RSV and smoke exposure also reduced protein phosphatase 2A (PP2A) and protein tyrosine phosphates (PTP1B) expression and activity. This is significant as these phosphatases counter smoke-induced inflammation and protease expression. Together, these findings show for the first time that recurrent RSV infection markedly enhances inflammation, apoptosis and tissue destruction in smoke-exposed mice. Indeed, these results indicate that preventing RSV transmission and infection has the potential to significantly impact on COPD severity and progression.

Respiratory Infections Cause the Release of Extracellular Vesicles: Implications in Exacerbation of Asthma/COPD

Background: Infection-related exacerbations of respiratory diseases are a major health concern; thus understanding the mechanisms driving them is of paramount importance. Despite distinct inflammatory profiles and pathological differences, asthma and COPD share a common clinical facet: raised airway ATP levels. Furthermore, evidence is growing to suggest that infective agents can cause the release of extracellular vesicle (EVs) in vitro and in bodily fluids. ATP can evoke the P2X7/caspase 1 dependent release of IL-1β/IL-18 from EVs; these cytokines are associated with neutrophilia and are increased during exacerbations. Thus we hypothesized that respiratory infections causes the release of EVs in the airway and that the raised ATP levels, present in respiratory disease, triggers the release of IL-1β/IL-18, neutrophilia and subsequent disease exacerbations.

Methods: To begin to test this hypothesis we utilised human cell-based assays, ex vivo murine BALF, in vivo pre-clinical models and human samples to test this hypothesis.

Results: Data showed that in a murine model of COPD, known to have increased airway ATP levels, infective challenge causes exacerbated inflammation. Using cell-based systems, murine models and samples collected from challenged healthy subjects, we showed that infection can trigger the release of EVs. When exposed to ATP the EVs release IL-1b/IL-18 via a P2X₇/caspase-dependent mechanism. Furthermore ATP challenge can cause a P2X₇ dependent increase in LPS-driven neutrophilia.

Conclusions: This preliminary data suggests a possible mechanism for how infections could exacerbate respiratory diseases and may highlight a possible signalling pathway for drug discovery efforts in this area.

Common community-acquired infections and subsequent risk of multiple myeloma: a population-based study

The role of bacteria and viruses as aetiological agents in the pathogenesis of cancer has been well established for several sites, including a number of haematological malignancies. Less clear is the impact of such exposures on the subsequent development of multiple myeloma (MM). Using the population-based U.S. Surveillance Epidemiology and End Results-Medicare dataset, 15,318 elderly MM and 200,000 controls were identified to investigate the impact of 14 common community-acquired infections and risk of MM. Odds ratios (ORs) and associated 95% confidence intervals (CIs) were adjusted for sex, age and calendar year of selection. The 13-month period prior to diagnosis/selection was excluded. Risk of MM was increased by 5-39% following Medicare claims for eight of the investigated infections. Positive associations were observed for several infections including bronchitis (adjusted OR 1.14, 95% CI 1.09-1.18), sinusitis (OR 1.15, 95% CI 1.10-1.20) pneumonia (OR 1.27, 95% CI 1.21-1.33), herpes zoster (OR 1.39, 95% CI 1.29-1.49) and cystitis (OR 1.09, 95% CI 1.05-1.14). Each of these infections remained significantly elevated following the exclusion of more than 6 years of claims data. Exposure to infectious antigens may therefore play a role in the development of MM. Alternatively, the observed associations may be a manifestation of an underlying immune disturbance present several years prior to MM diagnosis and thereby part of the natural history of disease progression.

Community-acquired infections associated with increased risk of lymphoplasmacytic lymphoma/Waldenström macroglobulinaemia

Emerging evidence supports the role of immune stimulation in the development of lymphoplasmacytic lymphoma/Waldenström Macroglobulinaemia (LPL/WM). Using the population-based Surveillance, Epidemiology End Results-Medicare database we investigated the exposure to 14 common community-acquired infections and subsequent risk of LPL/WM in 693 LPL/WM cases and 200 000 controls. Respiratory tract infections, bronchitis [odds ratio (OR) 1·56], pharyngitis (OR 1·43), pneumonia (OR 1·42) and sinusitis (OR 1·33) and skin infection, herpes zoster (OR 1·51) were all significantly associated with subsequent increased risk of LPL/WM. For each of these infections, the findings remained significantly elevated following the exclusion of more than 6 years of Medicare claims data prior to LPL/WM diagnosis. Our findings may support a role for infections in the development of LPL/WM or could reflect an underlying immune disturbance that is present several years prior to diagnosis and thereby part of the natural history of disease progression.

The effect of inhaled IFN-β on worsening of asthma symptoms caused by viral infections. a randomized trial

Rationale: Ex vivo, bronchial epithelial cells from people with asthma are more susceptible to rhinovirus infection caused by deficient induction of the antiviral protein, IFN-b. Exogenous IFN-b restores antiviral activity.

Objectives: To compare the efficacy and safety of inhaled IFN-b with placebo administered to people with asthma after onset of cold symptoms to prevent or attenuate asthma symptoms caused by respiratory viruses.

Methods: A total of 147 people with asthma on inhaled corticosteroids (British Thoracic Society Steps 2–5), with a history of virus-associated exacerbations, were randomized to 14-day treatment with inhaled IFN-b (n = 72) or placebo (n = 75) within 24 hours of developing cold symptoms and were assessed clinically, with relevant samples collected to assess virus infection and antiviral responses.

Measurements and Main Results: A total of 91% of randomized patients developed a defined cold. In this modified intention-to-treat population, asthma symptoms did not get clinically significantly worse
(mean change in six-item Asthma Control Questionnaire ,0.5) and IFN-b treatment had no significant effect on this primary endpoint, although it enhanced morning peak expiratory flow recovery (P = 0.033), reduced the need for additional treatment, and boosted innate immunity as assessed by blood and sputum biomarkers. In an exploratory analysis of the subset ofmore difficult-to-treat, Step 4-5 peoplewith asthma (n = 27 IFN-b; n = 31 placebo), Asthma Control Questionnaire-6 increased significantly on placebo; this was prevented by IFN-b (P = 0.004).

Conclusions: Although the trial did not meet its primary endpoint, it suggests that inhaled IFN-b is a potential treatment for virus-induced deteriorations of asthma in difficult-to-treat people with asthma and supports the needforfurther, adequately powered, trialsin this population. Clinical trial registered with www.clinicaltrials.gov (NCT 01126177).

The development of the PROMPT (PRescribing Optimally in Middle-aged People’s Treatments) criteria

BACKGROUND: Whilst multimorbidity is more prevalent with increasing age, approximately 30% of middle-aged adults (45-64 years) are also affected. Several prescribing criteria have been developed to optimise medication use in older people (≥65 years) with little focus on potentially inappropriate prescribing (PIP) in middle-aged adults. We have developed a set of explicit prescribing criteria called PROMPT (PRescribing Optimally in Middle-aged People's Treatments) which may be applied to prescribing datasets to determine the prevalence of PIP in this age-group.

METHODS: A literature search was conducted to identify published prescribing criteria for all age groups, with the Project Steering Group (convened for this study) adding further criteria for consideration, all of which were reviewed for relevance to middle-aged adults. These criteria underwent a two-round Delphi process, using an expert panel consisting of general practitioners, pharmacists and clinical pharmacologists from the United Kingdom and Republic of Ireland. Using web-based questionnaires, 17 panellists were asked to indicate their level of agreement with each criterion via a 5-point Likert scale (1 = Strongly Disagree, 5 = Strongly Agree) to assess the applicability to middle-aged adults in the absence of clinical information. Criteria were accepted/rejected/revised dependent on the panel's level of agreement using the median response/interquartile range and additional comments.

RESULTS: Thirty-four criteria were rated in the first round of this exercise and consensus was achieved on 17 criteria which were accepted into the PROMPT criteria. Consensus was not reached on the remaining 17, and six criteria were removed following a review of the additional comments. The second round of this exercise focused on the remaining 11 criteria, some of which were revised following the first exercise. Five criteria were accepted from the second round, providing a final list of 22 criteria [gastro-intestinal system (n = 3), cardiovascular system (n = 4), respiratory system (n = 4), central nervous system (n = 6), infections (n = 1), endocrine system (n = 1), musculoskeletal system (n = 2), duplicates (n = 1)].

CONCLUSIONS: PROMPT is the first set of prescribing criteria developed for use in middle-aged adults. The utility of these criteria will be tested in future studies using prescribing datasets.