Transmission of viral pathogens in a social network of university students: the eX-FLU study.

Previous research on respiratory infection transmission among university students has primarily focused on influenza. In this study, we explore potential transmission events for multiple respiratory pathogens in a social contact network of university students. University students residing in on-campus housing (n = 590) were followed for the development of influenza-like illness for 10-weeks during the 2012-13 influenza season. A contact network was built using weekly self-reported contacts, class schedules, and housing information. We considered a transmission event to have occurred if students were positive for the same pathogen and had a network connection within a 14-day period. Transmitters were individuals who had onset date prior to their infected social contact. Throat and nasal samples were analysed for multiple viruses by RT-PCR. Five viruses were involved in 18 transmission events (influenza A, parainfluenza virus 3, rhinovirus, coronavirus NL63, respiratory syncytial virus). Transmitters had higher numbers of co-infections (67%). Identified transmission events had contacts reported in small classes (33%), dormitory common areas (22%) and dormitory rooms (17%). These results suggest that targeting person-to-person interactions, through measures such as isolation and quarantine, could reduce transmission of respiratory infections on campus.

Severe morbidity among hospitalised adults with acute influenza and other respiratory infections: 2014-2015 and 2015-2016.

Our objective was to identify predictors of severe acute respiratory infection in hospitalised patients and understand the impact of vaccination and neuraminidase inhibitor administration on severe influenza. We analysed data from a study evaluating influenza vaccine effectiveness in two Michigan hospitals during the 2014-2015 and 2015-2016 influenza seasons. Adults admitted to the hospital with an acute respiratory infection were eligible. Through patient interview and medical record review, we evaluated potential risk factors for severe disease, defined as ICU admission, 30-day readmission, and hospital length of stay (LOS). Two hundred sixteen of 1119 participants had PCR-confirmed influenza. Frailty score, Charlson score and tertile of prior-year healthcare visits were associated with LOS. Charlson score >2 (OR 1.5 (1.0-2.3)) was associated with ICU admission. Highest tertile of prior-year visits (OR 0.3 (0.2-0.7)) was associated with decreased ICU admission. Increasing tertile of visits (OR 1.5 (1.2-1.8)) was associated with 30-day readmission. Frailty and prior-year healthcare visits were associated with 30-day readmission among influenza-positive participants. Neuraminidase inhibitors were associated with decreased LOS among vaccinated participants with influenza A (HR 1.6 (1.0-2.4)). Overall, frailty and lack of prior-year healthcare visits were predictors of disease severity. Neuraminidase inhibitors were associated with reduced severity among vaccine recipients.

Demographic and socioeconomic determinants of influenza vaccination disparities among university students.

BACKGROUND: The Advisory Committee on Immunization Practices encourages dormitory residents to receive influenza vaccination. To our knowledge, there are no studies that have directly examined factors associated with vaccination uptake among university students residing in dormitories. We therefore sought to examine the influence of demographic, social and health behaviours on influenza vaccination coverage among college dormitory students. METHODS: Cross-sectional analysis of baseline questionnaire data obtained from 845 eligible participants in a non-pharmaceutical intervention study for reducing influenza during the 2007-2008 influenza season. Significant predictors were identified through logistic regression analysis with generalised estimating equations to account for resident clustering. RESULTS: Increasing parental educational attainment was significantly associated with a trend in higher vaccination uptake among students: college graduate versus some college or less (OR 3.48, 95% CI 1.33 to 9.12) and some postgraduate education versus some college or less (OR 5.89, 95% CI 2.35 to 14.80) (trend test p<0.001). Adjusting for covariates, reported influenza vaccination for the 2007-2008 influenza season was strongly associated with reported influenza vaccination for the 2006-2007 influenza season (OR 16.38, 95% CI 9.28 to 28.91) and with speaking to a health professional about precautions to take against influenza (OR 2.95, 95% CI 1.42 to 6.13). CONCLUSIONS: The effect of parental educational status on vaccination rates can carry over to offspring, even among those who attain college student status. Programs targeting students who are employed on campus and who have never been vaccinated may be an especially effective way to increase vaccination rates, as both of these factors were significantly related to parental socioeconomic status in this study.

The increasing prominence of household transmission of hepatitis A in an area undergoing a shift in endemicity.

In the rapidly developing city of Almaty, Kazakhstan, rates of hepatitis A have fallen, but no data on prevalence of antibody to hepatitis A virus (anti-HAV) exist with which to interpret incidence data. In the autumn of 2001, we determined the anti-HAV prevalence among household and school contacts of hepatitis A cases. For contacts aged 0-4 years, 5-9 years, 10-14 years, 15-19 years, or 20-30 years, immune prevalences were 9, 12, 33, 33 and 77% respectively, among immediate-family household contacts and 15, 28, 49, 52 and 77% respectively, among community contacts. Child community contacts were more likely to be immune than their immediate-family household counterparts (odds ratio 2.0, 95% confidence interval 1.3-3.2). Almaty is experiencing an epidemiological shift in hepatitis A incidence. Feasible and effective prevention strategies using hepatitis A vaccine should be explored.

Person-to-person transmission of hepatitis A virus in an urban area of intermediate endemicity: implications for vaccination strategies.

Developing countries with an increasing hepatitis A disease burden may target vaccination to specific groups, such as young children, as an initial control strategy. To better understand transmission of hepatitis A virus in such countries, the authors prospectively studied household and day-care/school contacts of cases in Almaty, Kazakhstan. Overall, by the time of identification of symptomatic index cases, half of transmission had already occurred, having been detected retrospectively. The odds of household contacts' becoming infected were 35.4 times those for day-care/school contacts (95% confidence interval (CI): 17.5, 71.7). Within households, younger age of either index cases or susceptible contacts elevated the odds of secondary infection among susceptible contacts: The presence of a case under 6 years of age raised the odds 4.7 times (95% CI: 1.2, 18.7); and compared with contacts aged 14 years or older, the odds of infection were increased to 7.7 (95% CI: 1.5, 40.3) and 7.0 (95% CI: 1.4, 34.3) among contacts aged 0-6 years and 7-13 years, respectively. Young children are appropriate targets for sustainable hepatitis A vaccination programs in areas undergoing hepatitis A epidemiologic transition. If vaccine is determined to be highly effective postexposure and if it is feasible, vaccinating household contacts could be a useful additional control strategy.

Influenza virus carrying an R292K mutation in the neuraminidase gene is not transmitted in ferrets.

A model of influenza transmission has been established in ferrets in which wild-type influenza infection in a donor ferret can be transmitted sequentially to other ferrets. We have studied the transmission in ferrets of a clinical isolate of A/Sydney/5/97 (H3N2) carrying the neuraminidase 292K mutation compared with the corresponding wild-type virus from the same subject. Donor ferrets (n=four per group) were inoculated intranasally with mutant or wild-type virus and each housed with three naïve contact ferrets. All donor ferrets inoculated with wildtype virus were productively infected and transmitted virus to all 12 contacts, who in turn had high viral titres in their nasal washes. In contrast, only two of the donor ferrets inoculated with mutant virus were productively infected. There was little or no evidence that the two infected donor animals transmitted mutant virus to their contact animals. This ferret model has demonstrated that the mutant influenza virus with lysine at position 292 of the neuraminidase is of reduced infectivity and does not transmit under conditions in which the wild-type virus with arginine at position 292 readily transmits.

Respiratory illness caused by picornavirus infection: a review of clinical outcomes.

BACKGROUND: Respiratory infections result from invasion of the respiratory tract, mainly by viruses, and are the leading cause of acute morbidity in individuals of all ages worldwide. During peak season, picornaviruses cause 82% of all episodes of acute nasopharyngitis (the common cold), the most frequent manifestation of acute respiratory infection, and produce more restriction of activity and physician consultations annually than any other viral or bacterial source of respiratory illness. OBJECTIVE: This article reviews the clinical impact and outcomes of picornavirus-induced respiratory infections in specific populations at risk for complications. It also discusses the potential economic impact of the morbidity associated with picornavirus-induced respiratory infection. METHODS: Relevant literature was identified through searches of MEDLINE, OVID, International Pharmaceutical Abstracts, and Lexis-Nexis. The search terms used were picornavirus, rhinovirus, enterovirus, viral respiratory infection, upper respiratory infection, disease burden, economic, cost, complications, asthma, COPD, immunocompromised, elderly otitis media, and sinusitis. Additional publications were identified from the reference lists of the retrieved articles. CONCLUSIONS: Based on the clinical literature, picornavirus infections are associated with severe morbidity as well as considerable economic and societal costs. Future research should focus on identifying patterns of illness and the costs associated with management of these infections. New treatments should be assessed not only in terms of their ability to produce the desired clinical outcome, but also in terms of their ability to reduce the burden of disease, decrease health care costs, and improve productivity.

Ferrets as a transmission model for influenza: sequence changes in HA1 of type A (H3N2) virus.

Ferrets were used as an animal model to study whether controlled transmission of type A influenza is similar to human transmission when sequence changes in HA1 are used as the outcome. Ferrets were infected initially with A/Sydney/5/97 (H3N2) or A/LA/1/87 (H3N2) intranasally, and transmission chains were established by housing infected ferrets with noninfected ferrets with no influenza antibody titer against the infecting virus. Ferrets infected with A/Sydney were seronegative for A/Sydney and A/LA; ferrets infected with A/LA were seronegative for A/LA but had hemagglutination inhibition titers against A/Sydney. Titers of naturally transmitted influenza were higher than those after direct intranasal infection, but lymphocyte counts from nasal washes diminished with transmission. Ferrets infected with A/LA had 2 amino acid differences in HA1 after transmission through 5 ferret cohorts, but those infected with A/Sydney had none. The results show the value of the ferret model. A/LA resembled the transmission of influenza in humans when under antibody pressure.

Influenza vaccine effectiveness among elderly nursing home residents: a cohort study.

Outbreaks of influenza in nursing homes still occur, even when a large portion of residents have been inoculated with inactivated vaccine. Data were collected in 1991--1992 from 83 eligible skilled nursing homes located in southern Lower Michigan to determine the effectiveness of inactivated influenza vaccine in preventing influenza-like illness and influenza-associated pneumonia. Surveillance was conducted to identify the occurrence of influenza in the homes and, at the end of the season, specific data were gathered on all residents of homes with influenza activity. Age- and sex-adjusted estimates of vaccine effectiveness were calculated using Cox proportional hazards models for each nursing home. Estimates were pooled using precision-based weights calculated from data for each home. Vaccine was found to be 33% effective in preventing total respiratory illness (influenza-like illness and clinically diagnosed pneumonia). In prevention of pneumonia alone, vaccine was 43% effective. The estimate for prevention of pneumonia rose to 55% if the period under consideration was limited to the time of peak influenza activity. Given the number of eligible homes and the cohort methodology used, the results support continuation of current policy, encouraging use of vaccine in all nursing home residents.

Effectiveness of oseltamivir in preventing influenza in household contacts: a randomized controlled trial.

CONTEXT: Influenza virus is easily spread among the household contacts of an infected person, and prevention of influenza in household contacts can control spread of influenza in the community. OBJECTIVE: To investigate the efficacy of oseltamivir in preventing spread of influenza to household contacts of influenza-infected index cases (ICs). DESIGN AND SETTING: Randomized, double-blind, placebo-controlled study conducted at 76 centers in North America and Europe during the winter of 1998-1999. PARTICIPANTS: Three hundred seventy-seven ICs, 163 (43%) of whom had laboratory-confirmed influenza infection, and 955 household contacts (aged >/=12 years) of all ICs (415 contacts of influenza-positive ICs). INTERVENTIONS: Household contacts were randomly assigned by household cluster to take 75 mg of oseltamivir (n = 493) or placebo (n = 462) once daily for 7 days within 48 hours of symptom onset in the IC. The ICs did not receive antiviral treatment. MAIN OUTCOME MEASURE: Clinical influenza in contacts of influenza-positive ICs, confirmed in a laboratory by detection of virus shedding in nose and throat swabs or a 4-fold or greater increase in influenza-specific serum antibody titer between baseline and convalescent serum samples. RESULTS: In contacts of an influenza-positive IC, the overall protective efficacy of oseltamivir against clinical influenza was 89% for individuals (95% confidence interval [CI], 67%-97%; P<.001) and 84% for households (95% CI, 49%-95%; P<.001). In contacts of all ICs, oseltamivir also significantly reduced incidence of clinical influenza, with 89% protective efficacy (95% CI, 71%-96%; P<.001). Viral shedding was inhibited in contacts taking oseltamivir, with 84% protective efficacy (95% CI, 57%-95%; P<.001). All virus isolates from oseltamivir recipients retained sensitivity to the active metabolite. Oseltamivir was well tolerated; gastrointestinal tract effects were reported with similar frequency in oseltamivir (9.3%) and placebo (7.2%) recipients. CONCLUSION: In our sample, postexposure prophylaxis with oseltamivir, 75 mg once daily for 7 days, protected close contacts of influenza-infected persons against influenza illness, prevented outbreaks within households, and was well tolerated.

Effect of zanamivir on duration and resolution of influenza symptoms.

BACKGROUND: Zanamivir is a neuraminidase inhibitor, the first of a new class of drugs with potent, specific antiviral activity against influenza A and B. Administration by inhalation results in direct delivery to the respiratory tract, the principal site of viral replication. OBJECTIVE: This study was undertaken to determine the effectiveness of zanamivir on duration and resolution of influenza symptoms. METHODS: Using a method similar to that employed in amantadine treatment studies to obtain supporting evidence of efficacy for US Food and Drug Administration consideration, pooled data from 6 zanamivir phase II and III clinical trials involving primarily previously healthy adults were analyzed to categorize patients as accelerated resolvers (temperature <37.8 degrees C < or = 24 hours after dosing, plus a > or = 50% reduction in symptom score by 36 hours), early resolvers (temperature <37.8 degrees C < or = 36 hours after dosing), and nonaccelerated resolvers (febrile >36 hours after dosing). Patients in the accelerated and early categories were termed rapid resolvers; the others were slow resolvers. Patients recorded their symptom severity, temperature, ability to perform normal daily activities, and use of relief medication on a diary card. The primary end point of median time to alleviation of symptoms was also reexamined, with the additional requirement that patients were not taking relief medication when their symptoms were alleviated. This analysis was intended to control for the possible effect of relief medication on the primary end point. RESULTS: In the influenza-positive population (n = 1572), significantly more zanamivir-treated patients were rapid resolvers compared with those receiving placebo (807 [72%] vs 765 [64%], P < 0.001). Significant benefits of zanamivir treatment were observed in patients with a baseline temperature of > or = 37.8 degrees C (630 [68%] vs 595 [57%], P < 0.001) or > or = 38.3 degrees C (382 [67%] vs 365 [52%], P < 0.001) and in patients considered by their physi- cian to have severe symptoms at the start of therapy (252 [70%] vs 222 [63%], P = 0.02). Differences were even more apparent in patients with high-risk conditions (74% vs 53%, P = 0.014) and in those aged > or = 50 years (70% vs 54%, P = 0.005). Zanamivir treatment was also associated with a significant reduction in time to alleviation of symptoms with no use of relief medication. This was particularly noticeable in those aged > or = 50 years; time to alleviation was 13 days in patients receiving placebo and 6 days in patients receiving zanamivir (P < 0.001). In these trials, adverse events were reported at a similar frequency in patients receiving zanamivir and those receiving placebo. CONCLUSIONS: Zanamivir is more effective than placebo in patients with influenza at providing early symptom relief and a reduced duration of illness at a time when use of relief medication has ended. These benefits are seen across different patient groups but appear to be particularly marked in patients who are aged > or = 50 years, who have underlying illnesses, who are considered high risk, or who are more severely ill at the beginning of therapy.

Inhaled zanamivir for the prevention of influenza in families. Zanamivir Family Study Group.

BACKGROUND: As prophylaxis against influenza in families, amantadine and rimantadine have had inconsistent effectiveness, partly because of the transmission of drug-resistant variants from treated index patients. We performed a double-blind, placebo-controlled study of inhaled zanamivir for the treatment and prevention of influenza in families. METHODS: We enrolled families (with two to five members and at least one child who was five years of age or older) before the 1998-1999 influenza season. If an influenza-like illness developed in one member, the family was randomly assigned to receive either inhaled zanamivir or placebo. The family member with the index illness was treated with either 10 mg of inhaled zanamivir (163 subjects) or placebo (158) twice a day for 5 days, and the other family members received either 10 mg of zanamivir (414 subjects) or placebo (423) once a day as prophylaxis for 10 days. The primary end point was the proportion of families in which at least one household contact had symptomatic, laboratory-confirmed influenza. RESULTS: The proportion of families with at least one initially healthy household contact in whom influenza developed was smaller in the zanamivir group than in the placebo group (4 percent vs. 19 percent, P<0.001); the difference represented a 79 percent reduction in the proportion of families with at least one affected contact. Zanamivir provided protection against both influenza A and influenza B. A neuraminidase-inhibition assay and sequencing of the neuraminidase and hemagglutinin genes revealed no zanamivir-resistant variants. Among the subjects with index cases of laboratory-confirmed influenza, the median duration of symptoms was 2.5 days shorter in the zanamivir group than in the placebo group (5.0 vs. 7.5 days, P=0.01). Zanamivir was well tolerated. CONCLUSIONS: When combined with the treatment of index cases, prophylactic treatment of family members with once-daily inhaled zanamivir is well tolerated and prevents the development of influenza. In this study there was no evidence of the emergence of resistant influenza variants.

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.

Effect of Plasmodium falciparum parasitemia density on hemoglobin concentrations among full-term, normal birth weight children in western Kenya, IV. The Asembo Bay Cohort Project.

The relative importance of acute high-density versus persistent low-density Plasmodium falciparum parasitemia in contributing to the public health problem of malarial anemia remains unclear. The Asembo Bay Cohort Project in western Kenya collected monthly hemoglobin (Hb) and parasitologic measurements and biweekly assessments of antimalarial drug use among 942 singleton live births between 1992 and 1996. A mixed-model analysis appropriate for repeated measures data was used to study how time-varying parasitemia and antimalarial drug exposures influenced mean Hb profiles. Incidence of World Health Organization-defined severe malarial anemia was 28.1 per 1,000 person-years. Among children aged less than 24 months, concurrent parasitemia was significantly associated with lower mean Hb, especially when compared to children with no concurrent parasitemia. Increased densities of the 90-day history of parasitemia preceding Hb measurement was more strongly associated with mean Hb levels than concurrent parasitemia density. While the highest quartile of 90-day parasitemia history was associated with lowest mean Hb levels, children in the lowest 90-day exposure quartile still experienced significantly lower Hb levels when compared to children who remained parasitemia-free for the same 90-day period. The results highlight the importance of collecting and analyzing longitudinal Hb and parasitologic data when studying the natural history of malarial anemia.

Efficacy and safety of the neuraminidase inhibitor zanamivirin the treatment of influenza A and B virus infections.

The efficacy and safety of zanamivir, administered 2x or 4x daily over 5 days, was evaluated in the treatment of influenza infections. A total of 1256 patients entered the study; 57% of those randomized had laboratory-confirmed influenza infection. The primary end point, "alleviation of major symptoms," was created to evaluate differences in clinical impact. In the overall population with or without influenza infection, zanamivir reduced the median number of days to reach this end point by 1 day (P=.012 2x daily vs. placebo; P=.014 4x daily vs. placebo). The reduction was greater in patients treated within 30 h of symptom onset, febrile at study entry, and in defined high-risk groups. Zanamivir reduced nights of disturbed sleep, time to resumption of normal activities, and use of symptom relief medications. It was well tolerated. These results suggest that zanamivir can significantly reduce the duration and overall symptomatic effect of influenza.

Zanamivir in the prevention of influenza among healthy adults: a randomized controlled trial.

CONTEXT: The neuraminidase inhibitor zanamivir, a sialic acid analog administered directly to the respiratory tract, has been demonstrated in clinical studies to be effective in treatment of type A and B influenza. It has also been shown to prevent influenza infection and disease in an experimental model. OBJECTIVE: To examine the efficacy of zanamivir, administered once daily, in the prevention of influenza infection and disease. DESIGN: Double-blind, randomized, placebo-controlled trial. SETTING: Two midwestern university communities. PARTICIPANTS: A total of 1107 healthy adults (mean age [range], 29 [18-69] years) were recruited in November 1997, before the influenza season. INTERVENTION: At the start of the influenza outbreak, 554 subjects were randomized to receive placebo and 553 to receive zanamivir. The drug, 10 mg once per day, or identical placebo was administered by oral inhalation for a 4-week period. MAIN OUTCOME MEASURES: Illness occurrence was recorded by participants daily and records were evaluated weekly. Specimens were collected for viral isolation when symptoms were reported within 3 days of illness onset. Infection was also identified by testing paired serum samples for rise in antibody titer against the circulating influenza viruses. RESULTS: Zanamivir was 67% efficacious (95% confidence interval [CI], 39%-83%; P<.001) in preventing laboratory-confirmed clinical influenza meeting the case definition and 84% efficacious (95% CI, 55%-94%; P=.001) in preventing laboratory-confirmed illnesses with fever. All influenza infections occurring during the season, with or without symptoms, were prevented with an efficacy of 31% (95% CI, 4%-50%; P=.03). The nature and incidence of adverse events in the zanamivir group did not differ from placebo. Compliance with the once-daily dosage was high. CONCLUSIONS: Zanamivir administered once daily is efficacious and well tolerated in the prevention of influenza for a 4-week period in healthy adults.