Modeling Respiratory Syncytial Virus Adult Vaccination in the United States With a Dynamic Transmission Model.

BACKGROUND: Respiratory syncytial virus (RSV) is shown to cause substantial morbidity, hospitalization, and mortality in infants and older adults. Population-level modeling of RSV allows to estimate the full burden of disease and the potential epidemiological impact of novel prophylactics. METHODS: We modeled the RSV epidemiology in the United States across all ages using a deterministic compartmental transmission model. Population-level symptomatic RSV acute respiratory tract infection (ARI) cases were projected across different natural history scenarios with and without vaccination of adults aged ≥60 years. The impact of vaccine efficacy against ARIs, infectiousness and vaccine coverage on ARI incidence were assessed. The impact on medical attendance, hospitalization, complications, death, and other outcomes was also derived. RESULTS: Without a vaccine, we project 17.5-22.6 million symptomatic RSV ARI cases annually in adults aged ≥18 years in the US, with 3.6-4.8 million/year occurring in adults aged ≥60 years. Modeling indicates that up to 2.0 million symptomatic RSV-ARI cases could be prevented annually in ≥60-year-olds with a hypothetical vaccine (70% vaccine efficacy against symptomatic ARI and 60% vaccine coverage) and that up to 0.69 million/year could be prevented in the nonvaccinated population, assuming 50% vaccine impact on infectiousness. CONCLUSIONS: The model provides estimated burden of RSV in the US across all age groups, with substantial burden projected specifically in older adults. Vaccination of adults aged ≥60 years could significantly reduce the burden of disease in this population, with additional indirect effect in adults aged <60 years due to reduced transmissibility.

Erratum to: Frailty has a stronger association with inflammation than age in older veterans.

[This corrects the article DOI: 10.1186/s12979-016-0082-z.].

Influenza in the elderly: a mini-review.

Influenza is an important cause of morbidity and mortality in the elderly population each year. The often subtle clinical manifestations in the frail geriatric patients may not be recognized initially, impeding timely administration of antiviral treatment. The effectiveness of current influenza vaccines in the elderly population is often diminished by immune senescence. Increasing immunization rates among health-care workers and elderly caregivers, and finding more effective vaccines for the elderly people are likely to significantly improve disease prevention in this population at risk.

Effect of dehydroepiandrosterone sulfate on carnitine acetyl transferase activity and L-carnitine levels in oophorectomized rats.

Alteration in energy metabolism of postmenopausal women might be related to the reduction of dehydroepiandrosterone sulfate (DHEAS). DHEA and DHEAS decline with age, leveling at their nadir near menopause. DHEA and DHEAS modulate fatty acid metabolism by regulating carnitine acyltransferases and CoA. The purpose of this study was to determine whether dietary supplementation with DHEAS would also increase tissue L-carnitine levels, carnitine acetyltransferase (CAT) activity and mitochondrial respiration in oophorectomized rats. Plasma L-carnitine levels rose following oophorectomy in all groups (P < 0.0001). Supplementation with DHEAS was not associated with further elevation of plasma L-carnitine levels, but with increased hepatic total and free L-carnitine (P = 0.021 and P < 0.0001, respectively) and cardiac total L-carnitine concentrations (P = 0.045). In addition, DHEAS supplementation increased both hepatic and cardiac CAT activities (P < 0.0001 and P = 0.05 respectively). CAT activity positively correlated with the total and free carnitine levels in both liver and heart (r = 0.764, r = 0.785 and r = 0.700, r = 0.519, respectively). Liver mitochondrial respiratory control ratio, ADP:O ratio and oxygen uptake were similar in both control and supplemented groups. These results demonstrate that in oophorectomized rats, dietary DHEAS supplementation increases the liver and heart L-carnitine levels and CAT activities. In conclusion, DHEAS may modulate L-carnitine level and CAT activity in estrogen deficient rats. The potential role of DHEAS in the regulation of fatty acid oxidation in postmenopausal women is worthy of investigation.

Clinical signs and symptoms predicting influenza infection.

BACKGROUND: New antiviral drugs are available for the treatment of influenza type A and type B infections. In clinical practice, antiviral use has rarely been guided by antecedent laboratory diagnosis. Defined clinical predictors of an influenza infection can help guide timely therapy and avoid unnecessary antibiotic use. OBJECTIVE: To examine which clinical signs and symptoms are most predictive of influenza infection in patients with influenza-like illness using a large data set derived from clinical trials of zanamivir. METHODS: This analysis is a retrospective, pooled analysis of baseline signs and symptoms from phase 2 and 3 clinical trial participants. It was conducted in mainly unvaccinated (mean age, 35 years) adults and adolescents who had influenza-like illness, defined as having fever or feverishness plus at least 2 of the following influenza-like symptoms: headache, myalgia, cough, or sore throat who underwent laboratory testing for influenza. Clinical signs and symptoms were evaluated in statistical models to identify those best predicting laboratory confirmation of influenza. RESULTS: Of 3744 subjects enrolled with baseline influenza-like symptoms, and included in this analysis, 2470 (66%) were confirmed to have influenza. Individuals with influenza were more likely to have cough (93% vs 80%), fever (68% vs 40%), cough and fever together (64% vs 33%), and/or nasal congestion (91% vs 81%) than those without influenza. The best multivariate predictors of influenza infections were cough and fever with a positive predictive value of 79% (P<. 001). The positive predictive value rose with the increase in the temperature at the time of recruitment. CONCLUSION: When influenza is circulating within the community, patients with an influenza-like illness who have both cough and fever within 48 hours of symptom onset are likely to have influenza and the administration of influenza antiviral therapy may be appropriate to consider. Arch Intern Med. 2000;160:3243-3247.

Duration of antiviral prophylaxis during nursing home outbreaks of influenza A: a comparison of 2 protocols.

BACKGROUND: We performed a randomized trial of 2 protocols guiding the duration of antiviral chemoprophylaxis during outbreaks of influenza A in a rural, 700-bed nursing home for veterans and their spouses with 14 nursing units in 4 buildings. METHODS: Half of all residents volunteered to participate. Nursing units were randomized, and the effectiveness of short-term (minimum, 14 days and 7 days without the onset of a case in the building) vs long-term (minimum, 21 days and 7 days without the onset of a case in the 4-building facility) prophylaxis was compared using amantadine hydrochloride in the influenza seasons of 1991-1992 and 1993-1994 and rimantadine hydrochloride in the influenza season of 1994-1995. A "case" is defined as an incident of a respiratory tract illness and the isolation of an influenza virus organism. We compared the number of cases after the discontinuation of short- vs long-term chemoprophylaxis. Prospective surveillance identified residents with new respiratory tract symptoms, and specimens for viral cultures were obtained even in the absence of temperature elevation. RESULTS: We documented influenza A virus activity during 3 seasons (32, 68, and 12 patients, respectively). During the 1991-1992, 1993-1994, and 1994-1995 influenza seasons, the patients on 11 floors were assigned to receive short-term chemoprophylaxis and those on 10 floors were assigned to long-term chemoprophylaxis. Only in 1993-1994 did chemoprophylaxis extend beyond 14 or 21 days when new cases continued beyond 14 days. Amantadine-resistant strains were circulating at that time. None of the participants in the prospective, controlled study had influenza develop after the termination of short- or long-term chemoprophylaxis. CONCLUSION: Antiviral chemoprophylaxis can be administered for the longer duration of 14 days or, in the absence of new culture-confirmed illness in the nursing building, for 7 days.

Mortality following isolation of various respiratory viruses in nursing home residents.

OBJECTIVE: To compare mortality following isolation of influenza A to mortality following isolation of other respiratory viruses in a nursing home. SETTING: The Wisconsin Veterans Home, a 688-bed skilled nursing facility for veterans and their spouses. PARTICIPANTS: All residents with respiratory viral isolates obtained between 1988 and 1999. DESIGN: Thirty-day mortality was determined following each culture-proven illness. RESULTS: Thirty-day mortality following isolation of viral respiratory pathogens was 4.7% (15/322) for influenza A; 5.4% (7/129) for influenza B; 6.1% (3/49) for parainfluenza type 1; 0% (0/26) for parainfluenza types 2, 3, and 4; 0% (0/26) for respiratory syncytial virus (RSV); and 1.6% (1/61) for rhinovirus. CONCLUSIONS: Mortality following isolation of certain other respiratory viruses may be comparable to that following influenza A (although influenza A mortality might be higher without vaccination and antiviral agents). The use of uniform secretion precautions for all viral respiratory illness deserves consideration in nursing homes.

Reintroduction of influenza A to a nursing building.

We report an outbreak of influenza A from a four-building veterans' facility in King, Wisconsin. Influenza was isolated in 154 of 721 residents over a 121-day period. Building A had 2 cases, no isolates for 40 days, followed by 27 cases. Building B had 25 cases, no isolates for 75 days, followed by 4 cases. Building C had 23 cases, no isolates for 14 days, followed by 17 cases. Influenza A may be reintroduced to a nursing building. Surveillance with contingency plans for restarting of prophylaxis must continue for the duration of influenza in the community.

Report of an outbreak: nursing home architecture and influenza-A attack rates.

OBJECTIVE: To determine factors that might account for a significantly lower attack rate in a newly constructed nursing building during an epidemic of type A influenza. SETTING: A four-building, long-term care facility for veterans and their spouses, with an average daily census of 690. DESIGN: Prospective surveillance with retrospective analysis. PARTICIPANTS: Symptomatic residents submitting to viral culture. MEASUREMENTS: Number of respiratory illnesses and influenza cultures in consenting symptomatic residents. Building characteristics. RESULTS: An influenza A (H3N2) outbreak was culture-confirmed in 68 nursing home residents. Influenza A was isolated in 3/184 (2%) residents in Building A, 31/196 (16%) in Building B, 18/194 (9%) in Building C, and 16/116 (14%) in Building D. Denominators are average daily census during the outbreak. Building A had significantly fewer culture-confirmed cases than the other buildings (P < .001). Fewer residents in Building A, 47% compared with 61% in Buildings B, C, and D, were participants in a formal study of influenza. Eight of 15 respiratory illnesses identified during the outbreak that were not cultured occurred in Building A. These factors could not account for the difference in attack rates. Building A has a unique ventilation system, more square feet of public space per resident, and does not contain office space that serves the entire four-building facility. CONCLUSION: Our retrospective observation suggests that architectural design may influence the attack rate of influenza A in nursing homes.

Augmentation of influenza antibody response in elderly men by thymosin alpha one. A double-blind placebo-controlled clinical study.

Influenza remains a major cause of illness and death in elderly people despite current vaccination programs. One factor is an immunization failure rate in the elderly that may be as high as 50%. To test whether administration of thymosin alpha 1 would result in greater antibody production, we administered it (900 micrograms/m2 subcutaneously twice weekly for eight doses) in conjunction with the 1986 trivalent influenza vaccine. Ninety men (65-99 years old, mean age 77.3 years) were randomized double-blind to receive thymosin alpha 1 or placebo by the same schedule; the sera from 85 of these men were acceptable for analysis. The two groups were similar with respect to underlying disease, medications, and age. No toxicity was observed in either group. Antibody response rate was defined as a four-fold rise in antibody titer over 3-6 weeks following vaccination and was measured by an enzyme-linked immunosorbent assay (ELISA). Analysis was performed on treatment groups and subgroups divided by the mean age: the older group consisted of subjects aged 77 years and older, and the younger group those aged from 65-76 years. Baseline and change in absolute antibody levels were compared by t test and using age as a continuous variable by multiple regression analysis.(ABSTRACT TRUNCATED AT 250 WORDS)

Efficacy of an influenza hemagglutinin-diphtheria toxoid conjugate vaccine in elderly nursing home subjects during an influenza outbreak.

OBJECTIVE: To compare the efficacy of an influenza hemagglutinin-diphtheria toxoid conjugate vaccine with the commercially available influenza hemagglutinin-subunit vaccine in preventing influenza in older adults living in a nursing home. DESIGN: A prospective, randomized, double-blind vaccine trial with 5 months of follow-up after vaccination. SETTING: Fourteen Wisconsin nursing homes. PARTICIPANTS: Nursing home residents at least 65 years old who were able to give informed consent and were free of malignancy and not receiving immunosuppressive therapy. INTERVENTIONS: Participants received, by intramuscular injection, 0.5 mL of a trivalent influenza vaccine containing 15 micrograms each of A/Leningrad/360/86 (H3N2), A/Taiwan/1/86 (H1N1), and B/Ann Arbor/1/86 (HA) or 0.5 mL of an influenza vaccine containing the same antigens conjugated to diphtheria toxoid (HA-D). MEASUREMENTS: Blood was obtained pre- and 1 month post-vaccination to assess for any vaccine-induced antibody titer change. Clinical surveillance for respiratory illness was performed twice weekly for 5 months. A record was kept of all signs and symptoms of new respiratory illness, and a viral culture and acute and convalescent sera were obtained. RESULTS: 204 participants received HA and 204 received HA-D. Both groups had similar baseline antibody levels to all influenza antigens. HA-D recipients seroconverted more frequently based on serum neutralizing activity (P < 0.05), had a greater increase in geometric mean titer (GMT), and sustained the increase in antibody titer longer than HA recipients. Vaccine hemagglutinin recall was greater in a subset of HA-D recipients as measured by lymphocyte proliferative assays (P < 0.05). During an outbreak of influenza A (H3N2 A/Shanghai/11/87-like and A/Victoria/7/87-like), fewer HA-D (29/195) than HA (43/204) recipients had laboratory-confirmed infection (P = 0.053), and, of these, fewer HA-D-treated subjects had lower respiratory tract involvement (5/29 HA-D and 17/43 HA) (P = 0.022). CONCLUSIONS: HA-D was more immunogenic in institutionalized elderly recipients and produced greater protection from influenza infection. Superior protection may be due to HA-D's ability to stimulate and recruit antigen-presenting cells, thus enabling the recipient to achieve and maintain functional antibody titers.

Long-term use of oseltamivir for the prophylaxis of influenza in a vaccinated frail older population.

OBJECTIVES: To investigate the efficacy of once-daily oral oseltamivir for 6 weeks (Tamiflu) in prophylaxis against laboratory-confirmed clinical influenza in frail older subjects living in homes for seniors and to determine the safety and tolerability of long-term oseltamivir. DESIGN: Double-blind, placebo-controlled, parallel-group, randomized, multicenter study. SETTING: Thirty-one residential homes for seniors across United States and Europe. PARTICIPANTS: Five hundred forty-eight frail older occupants (mean age 81 years, >80% vaccinated). INTERVENTION: Prophylaxis with oseltamivir 75 mg or placebo once daily for 6 weeks, beginning when influenza was detected locally. MEASUREMENTS: The primary efficacy endpoint was laboratory-confirmed clinical influenza. RESULTS: Oseltamivir administration resulted in a 92% reduction in the incidence of laboratory-confirmed clinical influenza compared with placebo (placebo 12/272 (4.4%), oseltamivir 1/276 (0.4%); P = .002). Of subjects vaccinated against influenza, oseltamivir was 91% effective in preventing laboratory-confirmed clinical influenza (placebo 11/218 (5.0%), oseltamivir 1/222 (0.5%); P = .003). Oseltamivir use was associated with a significant reduction in the incidence of secondary complications (placebo 7/272 (2.6%), oseltamivir 1/276 (0.4%); P = .037). Although nearly all subjects were taking concomitant medication both before and during the study, oseltamivir was well tolerated. A similar incidence of adverse events, including gastrointestinal effects, occurred in both groups. There was no suppression of antibody response in oseltamivir recipients. CONCLUSION: Oral oseltamivir 75 mg once daily for 6 weeks effectively prevented clinical influenza in vaccinated frail older subjects using significant concomitant medications in a residential care setting. The treatment was well tolerated and provided additional protection to that afforded by vaccination.

Non-influenza respiratory viruses may overlap and obscure influenza activity.

OBJECTIVE: To report the number and timing of influenza A isolates, as well as overlapping respiratory viruses. Co-circulating respiratory viruses may obscure the determination of influenza activity. DESIGN: Prospective clinical surveillance for the new onset of respiratory illness followed by viral cultures during seven separate influenza seasons. SETTING: The Wisconsin Veterans Home, a skilled nursing facility for veterans and their spouses. RESULTS: Influenza A isolates were encountered in greater numbers than non-influenza A isolates during three seasons. Seasonal variability is striking. In December 1992, we identified a large outbreak of respiratory illness. Influenza type B was cultured from 102 residents. In December 1995, influenza A was cultured from 285 people in Wisconsin. At that time, we identified outbreaks of respiratory illness in two of our four buildings. Based on statewide data, we suspected an influenza outbreak; however, 26 isolates of parainfluenza virus type 1 were cultured with no influenza. The potential importance of culturing at the end of the season was demonstrated in 1991-1992 when an outbreak of respiratory syncytial virus (RSV) overlapped and extended beyond influenza A activity. CONCLUSIONS: When interpreting new clinical respiratory illnesses as a basis for declaring an outbreak of influenza A, clinicians should realize that co-circulating respiratory viruses can account for clinical illnesses. Clinicians might utilize healthcare dollars efficiently by performing cultures to focus the timing of influenza A chemoprophylaxis. Cultures could be performed when clinical outbreak criteria are approached to confirm an outbreak. Culturing of new respiratory illness could begin again before the anticipated discontinuation of prophylaxis (approximately 2 weeks).

Zanamivir: a review of clinical safety.

Preclinical and clinical studies have clearly demonstrated that zanamivir, a potent and highly selective inhibitor of the influenza A and B virus neuraminidase, has an impressive safety profile. This report describes the safety and tolerability findings from the clinical studies completed up to the 17 July 1998 involving over 6000 adult and adolescent patients from North America, Europe and the Southern Hemisphere. Serious adverse events from an ongoing Japanese clinical programme are also reported. Zanamivir was administered in various dose forms and frequencies and was found to have a comparable safety profile with placebo when given for both the treatment and prophylaxis of influenza-like illness. These findings were independent of age and underlying medical condition. 4152 patients received zanamivir and the most commonly reported adverse events were consistent with the signs and symptoms of influenza-like illness. Most of the adverse events were mild and did not result in patient withdrawal from the studies. Less than 1% of zanamivir and placebo recipients reported a serious adverse event. In addition, 490 healthy volunteers received zanamivir in clinical pharmacology studies. It was well tolerated and the incidence of adverse events was similar in zanamivir and placebo recipients. In addition, no clinically significant laboratory abnormalities were detected. Results from in vitro and in vivo animal studies suggest that zanamivir has low acute toxicity and no significant systemic toxicity or respiratory tract irritancy at plasma exposures more than 100-fold higher than those anticipated following clinical use. Neither genotoxic nor reproductive types of toxicity have been observed in toxicology studies at doses equal to 17 to 197 times the current therapeutic dose (20 mg/day). The characteristics of the molecule and the low systemic exposure indicate a very low potential for drug interactions with the inhaled route. Furthermore, repeated 600mg intravenous doses were well tolerated in healthy volunteers. The observed safety profile of zanamivir compares favourably with currently available agents with anti-influenza virus activity, such as rimantadine and amantadine, as well as GS4104, a neuraminidase inhibitor currently in phase III development. This may be attributed to the low systemic bioavailability of zanamivir, which is given by oral inhalation, direct to the primary site of viral replication. The potential advantages of this include a reduced risk of drug-drug interactions, other nontarget organ toxicities (e.g. brain) and drug clearance issues from both kidney and liver. Therefore, the safety profile of zanamivir supports its use in the management of influenza.

Zanamivir: a review of clinical safety in individuals at high risk of developing influenza-related complications.

Post-marketing experience shows zanamivir to be well tolerated in the general population for the treatment and prophylaxis of influenza type A and B infections. Individuals at high-risk of influenza have potentially more to gain from zanamivir therapy. We assessed safety and tolerability findings from treatment and prophylaxis studies in over 982 high-risk subjects. Eight treatment studies involving high-risk subjects have been conducted with zanamivir 10 mg twice daily for 5 days. The incidence and pattern of adverse events was similar in zanamivir and placebo recipients. Lower respiratory adverse events reported by recipients receiving zanamivir occurred at similar or lower frequencies to those receiving placebo. In one treatment study involving 525 patients with asthma or chronic obstructive pulmonary disease, zanamivir recipients had a small but significantly increased mean morning peak expiratory flow rate (PEFR) and evening PEFR compared with placebo during the treatment period (days 1 to 5). Eight prophylaxis studies have been conducted, five in family or community settings and three in nursing homes. Data from these studies demonstrate that zanamivir is well tolerated for prophylaxis. In nursing home studies, where 90% of participants were high risk, the pattern and incidence of adverse events were similar to that reported in otherwise healthy individuals, and similar to both placebo and rimantadine, a comparator in one study. In treatment and prophylaxis studies the incidence and pattern of adverse events in participants > or =65 years or with chronic underlying respiratory disorders was similar for zanamivir or placebo recipients. Overall, zanamivir was well tolerated and study drug discontinuations were low. A small number of deaths have been reported in studies of high-risk elderly individuals, but none were considered to be related to zanamivir. Thus clinical studies have demonstrated that zanamivir has a comparable safety profile in high-risk and otherwise healthy recipients. Approximately 1.72 million treatment courses of zanamivir were prescribed up to the end of January 2001. Many spontaneous adverse event reports received since marketing, a third of these from non-healthcare professionals, reflect the underlying condition being treated. However, a number of events have resulted in changes to the zanamivir prescribing information, including rare reports of bronchospasm, dyspnoea, rash, urticaria and allergic type reactions including facial and oropharyngeal oedema. The reported safety profile of zanamivir, for treatment and prophylaxis of high risk subjects with influenza type A and B infections supports its continued use in these individuals who are likely to benefit most.

Surveillance for respiratory illness in long-term care settings: detection of illness using a prospective research technique.

BACKGROUND: The overall frequency and severity of viral respiratory infections affecting residents of long-term care facilities (LTCFs) is not well described. This is due primarily to the cumbersome and expensive techniques required for adequate surveillance of respiratory illnesses and the associated costs and availability of a laboratory capable of the relevant and timely report of diagnostic tests. Here we describe our technique for surveillance of respiratory illness in the LTCF. Elements of it may serve as strategies for routine care. METHODS: Nurses were trained to record respiratory complaints and to track them using a histogram-based calendar charting system. For the research technique, all new illnesses during the winter months, no matter how minor, were sampled for viral culture. RESULTS: Influenza A and B, parainfluenza types 1 through 4, herpes simplex virus types 1 and 2, rhinovirus, and respiratory syncytial virus (RSV) were detected in the nursing homes studied. Outbreaks of influenza were documented annually by prospective surveillance. Outbreaks of parainfluenza type 1 and RSV indistinguishable clinically from influenza were detected. CONCLUSIONS: Intense surveillance for respiratory illness and viral pathogens using the described research technique identified viral activity reliably on an annual basis in several large LTCFs. Elements of the research protocol may be adapted for general use to create a cost-effective surveillance program for LTCFs that have limited resources. Such a technique is essential for implementing effective measures for outbreak prevention and control.

Outbreaks of influenza A and B in a highly immunized nursing home population.

BACKGROUND: Large outbreaks of influenza A and B may occur in nursing homes despite high resident vaccination rates, even when the vaccine strain is matched to the circulating strain. This study reports the occurrence of separate influenza A and B outbreaks in a nursing home where more than 85% of residents were vaccinated. METHODS: Prospective surveillance was used to identify symptomatic residents in a rural Wisconsin nursing home with 680 residents. Viral cultures were obtained from all consenting residents identified with new respiratory symptoms even in the absence of temperature elevation. A "case" refers to a resident with a respiratory illness and an influenza isolate. RESULTS: During the 1992-93 season, 86% of 670 total residents were vaccinated, 104 (15.5%) were cases with influenza B. During the 1993-94 season, 89% of 690 total residents were vaccinated, 68 (9.8%) were cases with influenza A. The antigenic matches between vaccine and epidemic strains were characterized as "identical or minimal difference" by the Centers for Disease Control and Prevention. CONCLUSIONS: There is still a need to protect residents from infectious secretions and for contingency plans to permit the rapid use of antiviral agents. Future efforts are needed to develop vaccines that provide greater protection and to improve staff vaccination rates.