Biomedical subjects
Publications and source records attributed to Stefan Gravenstein.
This study assessed the safety and immunogenicity of a pediatric formulation of the 2003-2004 inactivated, trivalent, split virion influenza vaccine, administered in a 2-dose schedule in healthy children ages 6-36 months, of whom 94% had protective titers (> or =1/40) to at least 1 antigen. The 2003-2004 split virion influenza vaccine was safe and immunogenic in young children.
OBJECTIVE: The purpose of the study was to determine whether a new method of scoring the Clock Drawing Test (CDT) is a reliable and valid method for identifying older adults with declining driving competence. DESIGN: Prospective cohort study. SETTING: An outpatient driving evaluation clinic. PARTICIPANTS: One hundred nineteen community-dwelling, active drivers with a valid driver's license, aged 60 and older referred for driving evaluation. MAIN OUTCOME MEASURES: The CDT and a driving test using a STISIM Drive simulator. RESULTS: The CDT showed a high level of accuracy in predicting driving simulation outcome (area under the receiver-operator curve, 0.90; 95% confidence interval, 0.82 to 0.95). CDT scoring scales were comparable and all correlations between CDT scores and driving performance were negative, implying that as the CDT score decreases, the number of errors increases. Interrater reliability of CDT scores was 0.95. Subjects scoring less than 5 out of 7 points on the CDT made significantly more driving errors, hazardous and in total (P<.001). CONCLUSIONS: The CDT can help establish problems with executive function and indicate the need for a formal driving evaluation. Our CDT scoring scale is a reliable, valid, and time-effective screening tool for identifying elderly drivers in need of further evaluation.
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The increasing threat of bioterrorism and continued emergence of new infectious diseases has driven a major resurgence in biomedical research efforts to develop improved treatments, diagnostics and vaccines, as well as increase the fundamental understanding of the host immune response to infectious agents. The availability of multiple mass spectrometry platforms combined with multidimensional separation technologies and microbial genomic databases provides an unprecedented opportunity to develop these much needed resources. An overview of current proteomic strategies applied to microbes and viruses considered potential bioterrorism agents is presented. The emerging area of immunoproteomics as applied to the development of new vaccine targets is also summarized. These powerful research approaches can generate a multitude of potential new protein targets; however, translating these proteomic discoveries to useful counter-bioterrorism products will require large collaborative research efforts across multiple basic science and clinical disciplines. A translational proteomic research paradigm illustrating this approach using influenza virus as an example is discussed.
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The objective of this study was to analyze the changes in the type 1 T cell response, including the CD4+ Th1 and CD8+ T cell responses, to influenza in the elderly compared with those in young adults. PBMC activated ex vivo with influenza virus exhibited an age-related decline in type 1 T cell response, shown by the decline in the frequency of IFN-gamma-secreting memory T cells specific for influenza (IFN-gamma+ ISMT) using ELISPOT or intracellular cytokine staining. The reduced frequency of IFN-gamma+ ISMT was accompanied by a reduced level of IFN-gamma secretion per cell in elderly subjects. Tetramer staining, combined with IFN-gamma ELISPOT, indicated that the decline in IFN-gamma+, influenza M1-peptide-specific T cells was not due to attrition of the T cell repertoire, but, rather, to the functional loss of ISMT with age. In addition, the decline in type 1 T cell response was not due to an increase in Th2 response or defects in APCs from the elderly. The expansion of influenza-specific CD8+ T cells in CTL cultures was reduced in the elderly. Compared with young subjects, frail elderly subjects also exhibited a blunted and somewhat delayed type 1 T cell response to influenza vaccination, which correlated positively with the reduced IgG1 subtype and the total Ab response. Taken together, these data demonstrate that there is a decline in the type 1 T cell response to influenza with age that may help explain the age-related decline in vaccine efficacy and the increases in influenza morbidity and mortality.
CONTEXT: Some, but not all, previous studies suggest that prenatal influenza exposure increases the risk of schizophrenia. These studies used dates of influenza epidemics and maternal recall of infection to define influenza exposure, suggesting that discrepant findings may have resulted from exposure misclassification. OBJECTIVE: To examine whether serologically documented prenatal exposure to influenza increases the risk of schizophrenia. DESIGN: Nested case-control study of a large birth cohort, born from 1959 through 1966, and followed up for psychiatric disorders 30 to 38 years later. SETTING: Population-based birth cohort. PARTICIPANTS: Cases were 64 birth cohort members diagnosed as having schizophrenia spectrum disorders (mostly schizophrenia and schizoaffective disorder). Controls were 125 members of the birth cohort, had not been diagnosed as having a schizophrenia spectrum or major affective disorder, and were matched to cases on date of birth, sex, length of time in the cohort, and availability of maternal serum. MAIN OUTCOME MEASURES: Archived maternal serum was assayed for influenza antibody in pregnancies giving rise to offspring with schizophrenia and matched control offspring. RESULTS: The risk of schizophrenia was increased 7-fold for influenza exposure during the first trimester. There was no increased risk of schizophrenia with influenza during the second or third trimester. With the use of a broader gestational period of influenza exposure-early to midpregnancy-the risk of schizophrenia was increased 3-fold. The findings persisted after adjustment for potential confounders. CONCLUSIONS: These findings represent the first serologic evidence that prenatal influenza plays a role in schizophrenia. If confirmed, the results may have implications for the prevention of schizophrenia and for unraveling pathogenic mechanisms of the disorder.
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OBJECTIVES: To compare a proprietary extract of American ginseng, CVT-E002, with placebo in preventing acute respiratory illness (ARI) in an institutional setting during the influenza season. DESIGN: Two randomized, double-blind, placebo-controlled trials conducted late in the 2000 (8 week) and 2000-2001 (12 week) influenza seasons. SETTING: Long-term care setting that included nursing home and assisted living at three sites. PARTICIPANTS: Eighty-nine (2000) and 109 (2000-2001) enrolled subjects, average age 81 and 83.5, respectively; 74% women. Approximately 90% had received influenza vaccine in each of the 2 years. INTERVENTION: Oral twice-daily administration of a proprietary ginseng extract, CVT-E002, 200 mg or placebo. MEASUREMENTS: ARI was defined as two new respiratory symptoms or one with a constitutional symptom. Confirmation of viral ARI was by culture (influenza or respiratory syncytial virus (RSV)) or serology for influenza. Laboratory safety monitoring was done at 0, 4, and 8 or 12 weeks. RESULTS: An intent-to-treat analysis of pooled data corrected for drug exposure time showed that the incidence of laboratory-confirmed influenza illness (LCII) was greater in placebo- (7 cases/101 subjects) than CVT-E002-treated (1/97) groups (odds ratio (OR)=7.73, P=.033). Combined data for LCII and RSV illness were also greater in placebo- (9/101) than CVT-E002-treated (1/97) groups (OR=10.50, P=.009), for an overall 89% relative risk reduction of ARI in the CVT-E002 group. CONCLUSION: CVT-E002 was shown to be safe, well tolerated, and potentially effective for preventing ARI due to influenza and RSV.
OBJECTIVES: To prospectively detect amantadine-resistant influenza when amantadine was used for influenza A outbreak control. DESIGN: Prospective clinical surveillance and viral culture of all new respiratory illnesses during the course of amantadine prophylaxis. SETTING: A 721-bed, 14-ward nursing home for veterans and spouses during an influenza A outbreak (1993-94). PARTICIPANTS: Residents of a veterans hospital and their spouses. MEASUREMENTS: Nasopharyngeal and throat viral culture. All residents with positive cultures who developed new respiratory symptoms while receiving or residing on a unit receiving amantadine prophylaxis had antiviral-resistance testing and polymerase chain reaction restriction analyses performed. RESULTS: Amantadine prophylaxis was administered sequentially on nine of 14 wards to all well residents for 14 to 31 days/ward to control influenza outbreaks between December 9, 1993, and January 28, 1994. Amantadine treatment was simultaneously provided to 29 ill residents. Between December 3, 1993, and January 22, 1994, 68 culture-positive cases of influenza A were detected. Twenty subjects were receiving or residing on units receiving amantadine prophylaxis. Amantadine sensitivity testing could be performed on 16 residents; 12 residents had amantadine resistant strains. Four of the 12 had not received any antiviral treatment. Illness onset ranged from 1 to 22 days after amantadine prophylaxis was begun on the individual's unit. Two ribonucleic acid (RNA) mutations in the gene coding the M2 protein transmembrane region were observed that were clustered in time and space. Isolates from two roommates, one receiving amantadine for 18 days and one on no antiviral, had identical RNA sequences. CONCLUSION: Antiviral resistance may be responsible for failure of prophylaxis in nursing home outbreaks. Strategies that use different classes of antivirals for prophylaxis and treatment may limit emergence and transmission of resistant virus.
Influenza A was cultured in 62 double rooms. The roommate was infected in 12 (19.4%). During 3,294 resident-seasons, influenza was cultured in 208 single rooms (6.3%). Those who lived in double rooms with a culture-positive roommate had a 3.07 relative risk (CI95, 1.61-5.78) of acquiring influenza.
PURPOSE: To determine whether granulocyte-macrophage colony-stimulating factor (GM-CSF) would improve response to influenza vaccination in cancer patients. PATIENTS AND METHODS: In a randomized, patient-blinded, placebo-controlled trial carried out in 1997 to 2000, 133 patients were stratified into five groups of treatment and disease. Single doses of standard split trivalent influenza vaccine and either placebo or 250 micro g of GM-CSF were administered at the same time. Hemagglutination inhibition assay titers were measured before and 4 weeks after vaccination. RESULTS: Standard analyses, which define response as at least a four-fold increase in titers, detect no effect of GM-CSF for any of the three influenza subtypes in the trivalent vaccines (P >or=.12). Analysis that includes the magnitude of the change in titers and combines responses of the subtypes suggests that the placebo group had the greater response (P =.051), thus indicating that GM-CSF does not improve response. Ancillary analyses show that response declines both with increasing age and with higher initial titers. The fraction of patients with at least a four-fold increase in titers was 0.36 (95% confidence interval, 0.29 to 0.42) CONCLUSION: A single 250- micro g dose of GM-CSF administered with the influenza vaccine does not improve response to vaccination. Response in cancer patients is low and declines as age and initial titer increase.
Influenza virus remains among the most important pathogens infecting elderly people. Vaccination is the most cost-effective strategy to reduce morbidity and mortality due to influenza. For persons who are not vaccinated or for whom vaccines fail to prevent influenza, there are 2 classes of efficacious drugs for treatment or chemoprophylaxis: M2 channel inhibitors and neuraminidase inhibitors. Effective treatment, however, must commence within 48 h of the onset of symptoms, which can create problems for patients who wait to see whether their symptoms worsen or improve. Older adults who have relocated to the congregate housing environments of assisted living and long-term care facilities deserve special consideration, because influenza exposure risks are different for this group. Strategies for control of influenza must combine preventive approaches, such as vaccination, educational approaches, and the introduction of policies that allow health care professionals anticipate, identify, and efficiently respond to influenza outbreaks.
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OBJECTIVES: To determine adverse clinical events and resource utilization associated with culture-positive influenza A in nursing home residents. DESIGN: A retrospective cohort study with cases and controls. SETTING: Seven hundred twenty-one-bed skilled nursing facility. PARTICIPANTS: One hundred fifty-four residents (21% of all residents) from whom influenza A was isolated during the 1997/98 season and matched controls. MEASUREMENTS: Baseline parameters, staff interventions, diagnostic tests, and adverse events were recorded from 60 days before to 60 days after specimen collection. The difference between each individual's before and after measurements determined excess utilization secondary to influenza. Controls were studied to determine time series effects. RESULTS: Baseline Minimum Data Set and nutritional parameters demonstrated significantly greater (P <.05) feeding dependency and lower serum albumin in the control group. Time series effects in the control group were negligible. Among cases, there were nine deaths within 30 days; among controls, there were four (chi2 P =.26). Within 30 days of onset, an average excess of 18 notations by nursing staff, one phone call to the physician, and one to family was noted per case. In half of cases, a nonscheduled physician visit was required. There was a 20% excess in physician orders for oxygen and bronchodilators. Chest x-rays were performed in half of the cases, and antibiotics were prescribed to half. Sixteen percent of cases had radiographic pneumonia, and 2% had congestive heart failure. The average cost for excess chest x-rays, laboratory services, antimicrobials, ambulance calls, hospital days, and emergency room and physician visits was $943.44. This does not include efforts by nursing home staff who accommodate functional decline on-site. CONCLUSION: An unexpected finding was that there were more impaired individuals who were less likely to have influenza detected or less likely to acquire influenza in the control group than in the influenza group. The morbidity, mortality, excess staff effort, and measured expenditure justify efforts to prevent influenza.
OBJECTIVE: To identify delayed prophylaxis from a pre-existing database and strategies to improve performance. SETTING: A skilled nursing facility with 14 floors (4 buildings). The "outbreak unit" was a 50- to 60-bed floor. METHODS: We performed surveillance during six seasons using one protocol. Prophylaxis was started when influenza was cultured in the building and 10% of residents on the floor had a new respiratory illness within 7 days. We defined delayed prophylaxis as four or more residents on a floor with positive cultures whose specimens had been collected within 5 days before the application of prophylaxis. RESULTS: We identified 14 examples of delayed prophylaxis. In three, delayed prophylaxis was related to the 3.9-day delay between culture collection and culture report There was a high degree of commonality among building attack rates within a season. During six seasons, the first case in the last building occurred 27 to 64 days after the first case in the facility. The two seasons with the greatest activity (68 and 154 cases, respectively) began with explosive, multi-floor outbreaks in a single building. The match between the circulating strain and the vaccine was good, except in 1997-1998 when there were seven examples of delayed prophylaxis. CONCLUSIONS: Influenza may involve buildings sequentially with a commonality of building attack rates. Explosive, multi-floor outbreaks early in the season could lead to a lower threshold for prophylaxis within a larger area when initial cases are encountered later in the season. This strategy could have prevented five examples of delayed prophylaxis. Rapid testing of multiple specimens while waiting for culture confirmation could have prevented three examples of delayed prophylaxis.
Anemia is a frequent problem among older persons, the prevalence of which may be particularly high in skilled-nursing facilities but recent data in this regard is lacking. The purpose of this study was to define the prevalence of anemia and its association with hospitalization in skilled-nursing home residents. We retrospectively reviewed randomly selected charts among five skilled-nursing facilities within the National Geriatrics Research Consortium (NGRC). Among 900 chronically residing patients with completed chart information, the mean and median ages were 79 years and 82 years, respectively. Eighty-seven percent of patients were 65 years or greater. Applying the World Health Organization criteria for anemia (hemoglobin <12 g/dl for women and hemoglobin <13 g/dl for men), we found a 6-month point prevalence of 48%. The hospitalization rate was higher among those with more severe anemia. Few residents were treated with recombinant erythropoietin therapy or red blood cell transfusion. Anemia is very common in the nursing home, and despite being associated with increased morbidity; it is, for the most part, untreated in this setting. With an increased understanding of erythropoiesis and the availability of recombinant growth factors, future studies should evaluate the causes and potential benefits of treatment in terms of quality of life, reduced morbidity and health economics.
BACKGROUND: Despite vaccination, influenza commonly causes morbidity and mortality in institutional settings. Influenza control with rimantadine and amantadine is limited by emergence and transmission of drug-resistant influenza A variants, ineffectiveness against influenza B, and toxicity. This study evaluated the efficacy and tolerability of zanamivir versus rimantadine for influenza outbreak control in long-term care facilities. METHODS: This double-blind, randomized, controlled study prospectively enrolled nursing home residents for 3 influenza seasons (1997 to 2000). Vaccine was offered to all subjects. Following influenza outbreak declaration, subjects were randomized to inhaled zanamivir 10 mg or standard of care (rimantadine 100 mg for influenza A or placebo for influenza B) once daily for 14 days. The proportion of randomized subjects developing symptomatic, laboratory-confirmed influenza during prophylaxis was the primary endpoint. RESULTS: Of 482 randomizations (238 zanamivir, 231 rimantadine, 13 placebo), 96% of subjects were elderly or had high-risk conditions; over 90% were vaccinated. Symptomatic, laboratory-confirmed influenza occurred in 3% of zanamivir subjects and 8% of rimantadine subjects during chemoprophylaxis (P = .038; additional protective efficacy for zanamivir over rimantadine = 61%). Since only 25 subjects were randomized during 2 influenza B outbreaks and none developed influenza, the influenza B data were excluded from further analysis. Zanamivir was well tolerated and unassociated with emergence of resistant virus; rimantadine-resistant variants were common. CONCLUSIONS: This is the first prospective, controlled study demonstrating effectiveness of chemoprophylaxis for influenza outbreak control. Zanamivir prevents symptomatic, laboratory-confirmed influenza more effectively than rimantadine, is unassociated with resistant virus, and has a favorable safety profile. Zanamivir is an appropriate alternative for influenza outbreak control among institutionalized vaccinated elderly.