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.

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.

Influenza: quantifying morbidity and mortality.

Because of their dramatic impact, morbidity and mortality associated with influenza have been recognized since at least the time of Elizabeth I of England. Excess mortality has been documented since 1889, and the infamous 1918 outbreak confirmed that influenza was truly one of the last major plagues. Despite the clear recognition of large clusters of influenza activity, it is still difficult to quantify precisely the total impact of influenza morbidity and mortality, since laboratory confirmation is required for exact diagnosis. Many methods have been developed to provide estimates of the mortality associated with influenza. These methods are usually predicated on establishing expected baseline rates of mortality. Deaths in excess of these rates are then calculated--and attributed to the circulating influenza virus. In this way, groups at high risk of mortality have been defined as the elderly and those with chronic conditions. Special-risk groups, such as those in institutions, have also been identified. The quantification of morbidity has required different approaches, and here community and family studies have made major contributions. In contrast to mortality, morbidity is most pronounced in children and young adults, and the diseases, although self-limited, are often quite severe. Although the size of the outbreaks varies, influenza infection can be documented annually. Thus, each year must be considered an influenza year.

Viral respiratory infections in the community: epidemiology, agents, and interventions.

Viral respiratory infections are a leading cause of acute morbidity in the community. The annual frequency of respiratory illness rises during the second year of life, falls during subsequent years, increases again during child-bearing years, then decreases with advancing age (although some increase may be seen in the elderly). In terms of restriction on activity and prompting of visits to physicians, the greatest number of illnesses are associated with rhinoviruses followed by influenza viruses. However, comparing rhinovirus and influenza, there is no doubt that influenza viruses produce more severe symptoms. In some years, when there is a major influenza outbreak, they may even be identified at greater frequency. Moreover, unlike with other viruses, severity of influenza infection is high at all ages, but especially in older individuals. Influenza vaccine, which has been available for half a century, has proved effective in preventing hospitalizations for pneumonia and influenza during outbreaks of influenza types A and B. The antiviral agents amantadine and rimantadine provide approximately equivalent, and significant, efficacy in protection against clinical illness resulting from influenza type A only. However, the potential for side effects is more marked with amantadine. Some studies have shown that the rate of treatment withdrawal is no greater with rimantadine than with placebo. As we enter the next century, we may well see improvements in influenza vaccines, as well as the advent of antiviral agents that are effective against both type A and type B influenza.

Decreasing trends in Reye syndrome and aspirin use in Michigan, 1979 to 1984.

The incidence of Reye syndrome has been decreasing in Michigan, perhaps as a result of decreased aspirin use among children. To evaluate possible changes in the frequency of aspirin use, 199 families in Tecumseh, MI, with children younger than 18 years of age were interviewed by telephone in February 1981 and again in February 1983. Based on the reported use of medications for colds or influenza between 1981 and 1983, fewer parents gave aspirin (56% v 25%), but acetaminophen use did not change (59% v 55%). Younger parents and parents who had heard of the association between aspirin and Reye syndrome were more likely to stop giving aspirin. More parents chose to use either no medication or medications containing neither aspirin nor acetaminophen (6% v 32%) for the treatment of colds or influenza. Approximately 90% of parents who chose not to give aspirin for fever also gave medications for colds or influenza that did not contain aspirin. These results suggest that fewer children are receiving aspirin during illnesses that may precede Reye syndrome. The associated decrease in the incidence of Reye syndrome tends to support the hypothesis that the use of aspirin increases the risk for the development of Reye syndrome.

Ribavirin utilization and clinical effectiveness in children hospitalized with respiratory syncytial virus infection.

Ribavirin was approved in early 1986 for treatment of illness associated with respiratory syncytial virus (RSV) infection in hospitalized children; however, the value of its use remains controversial. This investigation was undertaken to describe ribavirin utilization and to evaluate the effectiveness of ribavirin in reducing the period of hospitalization. All children with laboratory-confirmed RSV infection, hospitalized over seven epidemic periods at a single institution, were identified. Characteristics from the medical records of the 768 children and their course of hospitalization were evaluated as determinants of treatment with ribavirin. Very young age as well as diagnoses of congenital heart disease, certain pulmonary conditions, and failure to thrive were all significantly related to increased likelihood of treatment. Children requiring intensive care were likely to be treated; however, the most critically ill children, those who required mechanical ventilation, were not treated. Although these results were in keeping with treatment guidelines for the use of ribavirin, actual utilization declined significantly over the course of the evaluation. The effect of ribavirin treatment on the duration of hospitalization among children with community-acquired infection was evaluated in a multivariate model, which controlled for the effects of underlying conditions, measures of illness severity, and epidemic year. This analysis failed to demonstrate a benefit for ribavirin in reducing length of stay; in fact, ribavirin treatment was significantly associated with prolonged hospitalization. It was not likely that the explanation for ribavirin's association with prolonged hospitalization was that the most seriously ill children were treated; however, it was not possible to determine whether this association was due to an adverse effect of treatment or resulted from a perceived need to complete the course of therapy.

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.

Influenza vaccine effectiveness in preventing hospitalization among the elderly during influenza type A and type B seasons.

BACKGROUND: Influenza vaccine effectiveness evaluations were carried out among the elderly, as part of a demonstration established to estimate the value of including influenza vaccination as a covered Medicare benefit. METHODS: Cases hospitalized with pneumonia and influenza-related diagnoses during November through April were identified and group matched to randomly selected community controls. Data were collected from cases and controls on influenza vaccination status and other factors which could have confounded the association between vaccination and hospitalization. A community-based influenza surveillance programme was conducted each year to determine the timing and aetiology of influenza activity. Logistic regression analyses were carried out to evaluate the association of influenza vaccination with the likelihood of hospitalization. RESULTS: In 1990-1991, during the peak of the influenza type B outbreak, influenza vaccination was estimated to be 31% (95% CI: 4-51%) effective in reducing the likelihood of hospitalization. In 1991-1992, during the peak of the influenza type A(H3N2) epidemic, a nearly identical point estimate for vaccine effectiveness was demonstrated (32%, 95% CI: 7-50%). Identical analyses carried out each year during the periods of low or absent influenza activity failed to demonstrate a significant effect for vaccination in preventing hospitalization. CONCLUSION: Results indicated that a significant benefit for vaccination could be expected during both type A and type B influenza seasons.

Statistical procedures for estimating the community probability of illness in family studies: rhinovirus and influenza.

A statistical method is presented for determining acquisition rates of illness from community sources of infection and for distinguishing among viruses which are associated with different epidemic seasons. The new method consists of a computationally simple procedure for estimating the community transmission parameter and the standard error of the estimator. This method, as well as a previously developed maximum likelihood procedure, is applied to illness data as a means for distinguishing among broad patterns of illness acquisition. The periods evaluated are the rhinovirus, influenza A and influenza B seasons in Tecumseh, Michigan, for the years 1976-1980. Tecumseh households are stratified into exposure groups depending on age-group composition. Estimates are found for the risk differences of illness acquired from the community for households with different age-group distributions. Analysis of the Tecumseh data reveals that members of households with children are more apt than members of households without children to acquire illness associated with rhinovirus, influenza A and influenza B from the community. Members of households with just preschool children (and adults) are more apt than members of households with just school children (and adults) to acquire illness associated with rhinovirus and influenza B from the community. In contrast, members of households with just preschool children (and adults) are just as likely as members of households with just school children (and adults) to acquire illnesses associated with influenza A from the community.

Simulation studies of influenza epidemics: assessment of parameter estimation and sensitivity.

The influenza simulation model of Elveback et al is used to evaluate the accuracy of the maximum likelihood procedure of Longini et al for estimating the secondary attack rate in households. The sample population from the Tecumseh Respiratory Illness Study is mapped into the simulation model and simulations are carried out over a range of parameter values and conditions, some of which were derived from influenza seasons in Tecumseh and from the Seattle Flu Study for the years 1975-1980. The estimation procedure is found to be quite robust for parameter values preset within appropriate limits for influenza. However, a significant difference is found between the preset and estimated household contact parameter for epidemics of medium and high intensity when the preset value is zero. Incremental increases in the household contact parameter are shown to produce marked increases in the overall infection attack rate demonstrating that household spread is an important link in maintaining infection in other mixing groups such as schools, preschool groups and neighbourhood clusters of households.

Effectiveness of inactivated influenza vaccine among nursing home residents during an influenza type A (H3N2) epidemic.

OBJECTIVES: To evaluate the use of influenza vaccine in nursing homes and its effectiveness in reducing the likelihood of influenza-like illness. DESIGN: A retrospective case-control study with active identification of influenza infection. SETTING: All nursing homes in a seven-county study area in southern lower Michigan were eligible for participation. Analyses were based on data collected from 23 homes with documented influenza transmission. PARTICIPANTS: Persons aged 65 years or older who were residents of the nursing homes under study during the influenza type A(H3N2) outbreak in 1989-1990. MEASUREMENTS: Residents were identified as cases or controls based on occurrence of febrile respiratory illness meeting a case definition. Demographic and underlying illness information were gathered as were data on the use of influenza vaccine, antibiotics, and antivirals. Characteristics of the nursing homes were also recorded. Logistic regression analyses were carried out to determine vaccine effectiveness. MAIN RESULTS: Determinants of vaccine use were different from those observed in a parallel community-based study. In a multivariate model that considered the effects of resident and nursing home characteristics, vaccinated residents were significantly less likely than those who were not vaccinated to have an influenza-like illness (OR = .58 (95% CI, .43-.78), P < .001, imputed vaccine effectiveness estimate of 42%). Vaccination was more effective in younger residents (those aged 65 to 84) then in older residents (those older than 84 years). CONCLUSIONS: Influenza vaccination was effective in reducing the likelihood of influenza-like illness in nursing home residents. Effectiveness appeared to be related to age, which may function as a surrogate for related immunologic factors. Older nursing home residents should be targeted for newer vaccines and/or potential prophylactic use of antivirals.

Prevalence and intensity of Schistosoma haematobium infection in six villages of upper Egypt.

A cross-sectional survey for Schistosoma haematobium infection in 5,998 individuals, representing 31,803 persons in six rural villages of the Qena governorate, Upper Egypt, was completed. There were 2,223 persons (37.1%) excreting S. haematobium eggs identified by the nuclepore membrane filtration technique of a single urine specimen. Prevalence of infection ranged from 23.9% to 64.0% among the six villages. Quantitatively the overall geometric mean egg-count was 48.1 eggs/10 ml urine. A survey of proximal canals was conducted and 9 of 4,312 Bulinus snails were infected with schistosomes (0.21%). The stools of 2 of 507 adolescent males were positive for S. mansoni. No Biomphalaria snails were found. When these findings are compared to past studies, S haematobium prevalence appears to have substantially increased.

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.

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.

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.

Influenza vaccine use among an elderly population in a community intervention.

A community intervention program was carried out to promote influenza immunization among an elderly population, as part of a demonstration established to estimate the value of including influenza immunization as a Medicare-covered benefit. Potential recipients were informed of reasons for receiving vaccine and its availability at no cost, and physicians and others administering it were provided with educational materials and cost reimbursement. Data collected for annual evaluations of influenza vaccine effectiveness were used to evaluate the impact of the community intervention program on influenza immunization status and to determine the effects of age, gender, chronic health conditions, and smoking status on the likelihood of immunization. Results indicated that the intervention program had a statistically significant impact on increasing the likelihood of immunization among the elderly population living in the targeted area. The existence of certain chronic health conditions also predicted immunization, while the effect of current smoking on immunization was strongly negative. During the three years of vaccine promotion, use in those 65 years and older who resided in the intervention area increased from approximately 40% in 1989-1990 to over 56% in 1991-1992. With various incentives, including cost reimbursement through Medicare, influenza immunization can be markedly increased among elderly beneficiaries.

The value of influenza and pneumococcal vaccines in the elderly.

Influenza and pneumococcal vaccines have been available for decades and have repeatedly been shown to be efficacious in healthy adults. However, for both vaccines, efficacy in high risk populations and older individuals does not seem to be as great, leading to reluctance to use them as recommended. Recent observational studies in older individuals have confirmed and quantified the effectiveness of the 2 vaccines in situations of actual use. Economic data indicate that under realistic situations they are likely to reduce costs for healthcare systems. Societal benefits are now also established. While it may be useful to confirm the cost savings in additional systems of healthcare, the current emphasis should be to devise strategies to increase use of the vaccines.

Individual and community impact of influenza.

Influenza has been recognised as a distinct entity for centuries because of its profound effect on respiratory morbidity and mortality, although the full burden of the disease has been difficult to determine. The population groups most affected by influenza morbidity and mortality have also been recognised for years and are strongly related to the viral type or subtype circulating. Studies in the US suggest that the traditional pneumonia and influenza (P&I) mortality rate underestimates the total impact of influenza on mortality by a factor of approximately 3.8. Observations in different parts of the world confirm that mortality associated with P&I is not limited to specific countries. Vaccination not only reduces the severity of illness and death from P&I, but also reduces all-cause mortality, thus confirming these observations. Estimates of overall morbidity vary widely, depending on the methods used in various observational studies. The actual impact of influenza is likely to be within this range of estimates, but recent vaccination studies suggest the possibility of much higher rates of morbidity than previously estimated.

The clinical efficacy of influenza vaccination.

Inactivated influenza vaccine was developed approximately 50 years ago. The formulation has been continually improved, and its efficacy in preventing morbidity in healthy adults repeatedly demonstrated. Whether or not the vaccine is able to prevent hospitalisation and other complications of influenza in older individuals has been resolved by recent observational studies. During period of influenza virus circulation, the vaccine has also been shown to be effective in preventing hospitalisation and, in some cases, death from all causes and specific causes such as all respiratory conditions. Antivirals are also available for use against type A influenza, and may be especially valuable when antigenic change in the virus occurs. Now that questions regarding clinical effectiveness have been answered, vaccine and antivirals should certainly be more extensively used then in the past. The determinations of positive clinical effectiveness, which are based on observations of actual use of the vaccine, can form a basis for calculation of cost effectiveness.