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In this dose-ranging study 220 seniors who had received the 23-valent pneumococcal polysaccharide (PnPS) vaccine at least 5 years prior to enrollment were assigned to receive one of four volumes (0.1, 0.5, 1 or 2 ml) of 7-valent pneumococcal conjugate (PnC) vaccine or a 0.5 ml dose of 23-valent PnPS vaccine. All participants received a reduced challenge dose of 0.1 ml of PnPS vaccine 1 year after enrollment. There was evidence of a dose response to PnC vaccine and antibody levels in the 1 ml PnC group tended to be significantly higher than in the PnPS group. A booster response to the challenge vaccination was not observed. Administration of a 1 ml dose of PnC vaccine is more immunogenic than 0.5 ml of PnPS vaccine in elderly adults previously vaccinated with PnPS vaccine.

Objectives: Children <9 years of age do not respond optimally to a first dose of trivalent inactivated influenza vaccine, and so 2 doses of trivalent inactivated influenza vaccine are recommended for children <9 years of age who are being vaccinated for the first time. We conducted a population-based retrospective cohort study to evaluate compliance with the 2-dose trivalent inactivated influenza vaccine recommendations., Population and Setting: We evaluated 125,928 children 6 months through 8 years of age who were enrolled in health maintenance organizations in the United States participating in the Vaccine Safety Datalink project and who received their first dose of trivalent inactivated influenza vaccine in the 2001-2002, 2002-2003, or 2003-2004 influenza seasons., Results: Compliance with the 2 dose recommendations varied by age group and influenza season. Among children 6 to 23 months of age, the proportion of first-vaccinated children who received a second vaccination was 44% in 2001-2002, 54% in 2002-2003, and 29% in 2003-2004. Among children 2 to 8 years of age, the corresponding proportions were 15%, 24%, and 12%, respectively. In all seasons, compliance with the second vaccination was highest in children first vaccinated by mid-November., Conclusions: The majority of children who received their first dose of trivalent inactivated influenza vaccine did not complete the 2-dose series. The recently expanded recommendation for universal vaccination of children 6 to 59 months of age and their household contacts will substantially increase the number of children targeted for a first influenza vaccination. Noncompliance with the 2-dose trivalent inactivated influenza vaccine series may be associated with suboptimal protection against infection, which may impact the magnitude of the direct and indirect benefits achieved by the vaccination program.

Background: We assessed the effects of an influenza season on patients with COPD. Data from 2,215 veterans in a multicenter, randomized, double-blind influenza vaccine efficacy study were analyzed for changes in spirometric and functional status, comparing patients with laboratory-documented influenza (LDI)-caused illness, non-LDI-caused respiratory illness, or no illness, and for association with influenza vaccination., Methods: Patients received either IM trivalent inactivated influenza virus vaccine (TIV) plus intranasal trivalent, live attenuated, cold-adapted influenza virus vaccine (TC) or TIV plus intranasal placebo (TP). We performed spirometry, measured the chronic lung disease severity index (CLDSI) score to assess functional status and well-being, and tested for influenza virus infection., Results: Worsening in FEV(1), percentage of predicted FEV(1), and CLDSI score (p < 0.001) was associated with acute respiratory illness in 585 illnesses including 94 LDI-caused illnesses. LDI-caused illness was more likely to be associated with worsening in FEV(1) and CLDSI score acutely than non-LDI-caused illness (p < 0.01). Logistic regression showed acute respiratory illness (odds ratio [OR], 1.78; 95% confidence limit [CL], 1.40 to 2.26) to be associated with worsening in CLDSI score, and receipt of TC (OR, 1.39; 95% CL, 1.10 to 1.74) and no illness (OR, 0.70; 95% CL, 0.53 to 0.91 for acute respiratory illness) to be associated with better CLDSI score at the end of the study. Hospitalization was more frequent in patients with acute respiratory illness (p < 0.0001)., Conclusions: Acute respiratory illness was associated with increased health-care utilization and obstruction to airflow, and worse functional status and well-being. At the end of the study, receipt of TC was associated with improvement and acute respiratory illness was associated with worsening in functional status and well-being.

Background: Numerous observational studies have reported that seniors who receive influenza vaccine are at substantially lower risk of death and hospitalization during the influenza season than unvaccinated seniors. These estimates could be influenced by differences in underlying health status between the vaccinated and unvaccinated groups. Since a protective effect of vaccination should be specific to influenza season, evaluation of non-influenza periods could indicate the possible contribution of bias to the estimates observed during influenza season., Methods: We evaluated a cohort of 72,527 persons 65 years of age and older followed during an 8 year period and assessed the risk of death from any cause, or hospitalization for pneumonia or influenza, in relation to influenza vaccination, in periods before, during, and after influenza seasons. Secondary models adjusted for covariates defined primarily by diagnosis codes assigned to medical encounters., Results: The relative risk of death for vaccinated persons compared with unvaccinated persons was 0.39 [95% confidence interval (95% CI), 0.33-0.47] before influenza season, 0.56 (0.52-0.61) during influenza season, and 0.74 (0.67-0.80) after influenza season. The relative risk of pneumonia hospitalization was 0.72 (0.59-0.89) before, 0.82 (0.75-0.89) during, and 0.95 (0.85-1.07) after influenza season. Adjustment for diagnosis code variables resulted in estimates that were further from the null, in all time periods., Conclusions: The reductions in risk before influenza season indicate preferential receipt of vaccine by relatively healthy seniors. Adjustment for diagnosis code variables did not control for this bias. In this study, the magnitude of the bias demonstrated by the associations before the influenza season was sufficient to account entirely for the associations observed during influenza season.

Background: Functional status limitations may be associated with both an increased risk of death and a decreased likelihood of influenza vaccination, and so may confound the association of influenza vaccination and risk of all cause mortality in seniors., Methods: We conducted a nested case-control study of persons >or=65 years of age that included 252 cases who died during an influenza season and 576 age-matched controls. We identified functional limitations by medical record review, and compared the effect of adjustment for those factors with that of adjustment for disease covariates defined by diagnosis codes, using methods reported by previous influenza vaccine effectiveness studies, on the association of influenza vaccination and risk of death., Results: Functional limitations, such as requiring assistance for bathing, were highly prevalent in cases, even in the subgroup defined as free of comorbidity by diagnosis code criteria, and were associated with a decreased likelihood of vaccination among controls. Adjustment for functional limitations resulted in an estimate of the relative risk of death in vaccinated persons compared with unvaccinated persons that was closer to the null [odds ratio (OR), 0.71; 95% confidence interval (95% CI), 0.47-1.06] than the unadjusted estimate (OR, 0.59; 95% CI, 0.41-0.83). In contrast, adjustment for diagnosis code covariates moved the estimate further from the null (OR, 0.45; 95% CI, 0.30-0.68)., Conclusions: Functional limitations appear to be important confounders of the association of vaccination and risk of death, while adjustment for diagnosis code covariates did not control for a healthy vaccinee bias. Further research is needed on methods to reduce the influence of bias in observational studies of influenza vaccine effectiveness.

Objectives: To compare influenza and pneumococcal vaccination rates of older veterans with those of nonveterans and to compare vaccination rates of veterans who receive care at U.S. Department of Veterans Affairs (VA) medical centers with those of veterans who do not., Design: Cross-sectional population-based study., Setting: United States and territories., Participants: Persons aged 65 and older who participated in the 2003 Behavioral Risk Factor Surveillance System., Measurements: Telephone survey of sociodemographics factors, including veteran status and VA care, health and behavioral characteristics, and influenza and pneumococcal vaccine use., Results: Thirty percent of adults aged 65 and older were veterans, and 21% of veterans reported receiving care at VA health facilities. Veterans, especially VA users, were older and described poorer self-perceived health than nonveterans. Influenza and pneumococcal vaccination rates were higher for veterans than for nonveterans (74% vs 68% and 68% vs 63%, respectively, P < .001 for both) and for VA users than non-VA users (80% vs 72% and 81% vs 64%, respectively, P < .001 for both). For veterans, VA care was independently associated with influenza (odds ratio (OR) = 1.8, 95% confidence interval (CI) = 1.5-2.2) and pneumococcal (OR = 2.4, 95% CI = 2.0-2.9) vaccine use after adjusting for sociodemographics factors, perceived health status, diabetes mellitus, asthma, and smoking. Current smoking and black race were independent predictors of low influenza vaccine uptake., Conclusion: VA care was associated with improved influenza and pneumococcal vaccine coverage, although vaccination rates for all elderly veterans fell short of Healthy People 2010 goals. Increased efforts to reach undervaccinated groups, particularly blacks and smokers, are warranted.

There is little information on the safety of administration of a third dose of pneumococcal polysaccharide vaccine (PPV). The authors conducted a retrospective assessment of 316,995 adult members of three health maintenance organizations who had received one, two, or three PPV doses. Medical encounters associated with diagnosis codes potentially indicative of an injection site reaction in the week following a first, second, or third PPV dose were identified. These presumptive events occurred in 0.3% (911/279504) of the first PPV group, 0.7% (257/36888) of the second PPV group, and 0.5% (3/603) of the third PPV group (p>0.5 for both comparisons with the third PPV group). These findings do not suggest that a third PPV dose is associated with an increased risk of medically attended injection site reactions compared with a first or second PPV dose.

Influenza causes annual worldwide epidemics of respiratory disease. Currently, the United States and many other countries recommend influenza vaccination for persons who are at high risk for influenza-related complications. This commentary explores the potential benefits of a policy advocating universal annual influenza vaccination and outlines obstacles that need to be overcome to make such a recommendation feasible. The 5-year experience of a free influenza vaccination program for everyone > or =6 months of age in the Canadian province of Ontario is reviewed.

Objectives: To describe baseline characteristics and clinical outcomes of older adults with pneumococcal bacteremia, compare the frequency of serious outcomes according to pneumococcal vaccination status, and assess factors associated with mortality., Design: Population-based case-series., Setting: Group Health Cooperative, a health maintenance organization in Washington State., Participants: Community-dwelling adults aged 65 and older with a first episode of pneumococcal bacteremia between 1988 and 2002., Measurements: Demographic characteristics, underlying medical conditions, vaccination status, and clinical outcomes, including death, hospitalization, length of hospital stay, and postdischarge care, were assessed using chart review., Results: The mean age of the 200 elderly patients with pneumococcal bacteremia was 78; 61% were female. Forty percent had had chart-documented pneumococcal vaccination before the onset of bacteremia. The spectrum of clinical severity and consequences was broad. Ten percent were treated as outpatients. Of the 90% who were hospitalized, 16% were admitted to the intensive care unit. All-cause mortality at 30 days was 11%. Of survivors, 23% were discharged with home services, and another 20% were discharged to a nursing home. After controlling for age, sex, and pneumococcal vaccination status, predictors of death included coronary artery disease (odds ratio (OR)=4.6, 95% confidence interval (CI)=1.4-14.5) and immunocompromising conditions (OR=5.0, 95% CI=1.6-15.7). Outcomes were similar in patients who did and did not receive pneumococcal vaccination., Conclusion: In this elderly group, pneumococcal bacteremia was associated with substantial morbidity, mortality, and loss of independence. Coronary artery disease and immunocompromising conditions were independent predictors of death.

Background: The incidence and severity of herpes zoster and postherpetic neuralgia increase with age in association with a progressive decline in cell-mediated immunity to varicella-zoster virus (VZV). We tested the hypothesis that vaccination against VZV would decrease the incidence, severity, or both of herpes zoster and postherpetic neuralgia among older adults., Methods: We enrolled 38,546 adults 60 years of age or older in a randomized, double-blind, placebo-controlled trial of an investigational live attenuated Oka/Merck VZV vaccine ("zoster vaccine"). Herpes zoster was diagnosed according to clinical and laboratory criteria. The pain and discomfort associated with herpes zoster were measured repeatedly for six months. The primary end point was the burden of illness due to herpes zoster, a measure affected by the incidence, severity, and duration of the associated pain and discomfort. The secondary end point was the incidence of postherpetic neuralgia., Results: More than 95 percent of the subjects continued in the study to its completion, with a median of 3.12 years of surveillance for herpes zoster. A total of 957 confirmed cases of herpes zoster (315 among vaccine recipients and 642 among placebo recipients) and 107 cases of postherpetic neuralgia (27 among vaccine recipients and 80 among placebo recipients) were included in the efficacy analysis. The use of the zoster vaccine reduced the burden of illness due to herpes zoster by 61.1 percent (P<0.001), reduced the incidence of postherpetic neuralgia by 66.5 percent (P<0.001), and reduced the incidence of herpes zoster by 51.3 percent (P<0.001). Reactions at the injection site were more frequent among vaccine recipients but were generally mild., Conclusions: The zoster vaccine markedly reduced morbidity from herpes zoster and postherpetic neuralgia among older adults., (Copyright 2005 Massachusetts Medical Society.)

In a phase I/II dose escalation study, varying volumes (0.1 ml, 0.5 ml, 1.0 ml and 2.0 ml) of 7-valent pneumococcal conjugate vaccine (PCV) (Prevnar or 0.5 ml of 23-valent pneumococcal polysaccharide vaccine (PPV) were administered to 220 adults 70 through 79 years of age previously vaccinated with 0.5 ml PPV at age 65 years or above and at least 5 years previously. Fever was uncommon and did not vary by study group. The rate of local reactions increased with higher volumes of PCV and the rate following 2.0 ml of PCV was comparable to that following 0.5 ml PPV.

Background: Although Escherichia coli is a well-recognized cause of urinary tract infection in seniors, little is known about the burden of invasive E. coli infection in this population., Methods: We conducted a population-based cohort study of 46,238 noninstitutionalized Group Health Cooperative members>or=65 years of age to ascertain incidences of community-onset E. coli bacteremia and, for comparison, pneumococcal bacteremia, and we then performed a case-control study to identify risk factors for community-onset E. coli bacteremia., Results: The overall rate of community-onset E. coli bacteremia in the study cohort was 150 cases/100,000 person-years, which was approximately 3 times higher than the rate of pneumococcal bacteremia. In the case-control study, urinary catheterization and urinary incontinence were the only factors associated with an increased risk of E. coli bacteremia in men (62 cases), whereas cancer, renal failure, congestive heart failure, coronary artery disease, and urinary incontinence were associated with an increased risk of E. coli bacteremia in women (119 cases)., Conclusions: E. coli appears to be the leading cause of community-onset bacteremia in seniors, and, on the basis of these rates, we estimate that 53,476 cases occur in noninstitutionalized seniors each year in the United States. Community-onset E. coli bacteremia in seniors is, therefore, an infection of public health importance.

We used a Monte Carlo mathematical model to calculate the net economic returns (cost-benefit analysis) from annually vaccinating children against influenza. The model included cohorts of 1000 children in three different age groups (6-23 months, 6-59 months, and 5-14 years), with different proportions of children with high risk conditions (100, 10, and 0%). Vaccinating cohorts of 100% high risk children in all three age groups produced median net savings, regardless of cost of vaccination examined (US dollar 30-60/dose administered). Median threshold vaccination costs for cohorts containing 10% high risk children were US dollar 48, 46, and 45 per dose administered for age groups 6-23 months, 6-59 months, and 5-14 years, respectively (US dollar/dose administered below these thresholds generate net savings). For all cohorts, for the range of cost per dose administered examined, the 5th percentiles were net costs. The probability of death, though rare, was the most influential distribution in the model. The number of high-risk children that receive influenza vaccine should be maximized to achieve improved health outcomes as well as cost savings.

Background: Pneumonia is recognized as a leading cause of morbidity in seniors. However, the overall burden of this disease--and, in particular, the contribution of ambulatory cases to that burden--is not well defined. To estimate rates of community-acquired pneumonia and to identify risk factors for this disease, we conducted a large, population-based cohort study of persons aged >or=65 years that included both hospitalizations and outpatient visits for pneumonia., Methods: The study population consisted of 46,237 seniors enrolled at Group Health Cooperative who were observed over a 3-year period. Pneumonia episodes presumptively identified by International Classification of Diseases, Ninth Revision, Clinical Modification codes assigned to medical encounters were validated by medical record review. Characteristics of participants were defined by administrative data sources., Results: The overall rate of community-acquired pneumonia ranged from 18.2 cases per 1000 person-years among persons aged 65-69 years to 52.3 cases per 1000 person-years among those aged >or=85 years. In this population, 59.3% of all pneumonia episodes were treated on an outpatient basis. In multivariate analysis, risk factors for community-acquired pneumonia included age, male sex, chronic obstructive pulmonary disease, asthma, diabetes mellitus, congestive heart failure, and smoking., Conclusions: On the basis of these data, we estimate that roughly 915,900 cases of community-acquired pneumonia occur annually among seniors in the United States and that approximately 1 of every 20 persons aged >or=85 years will have a new episode of community-acquired pneumonia each year.

Background: To determine how patient attitudes, beliefs, knowledge, and sociodemographic characteristics relate to influenza vaccine acceptance in an older patient population., Methods: We conducted a mail survey of patients enrolled in a geriatrics clinic at a university-affiliated county hospital in Seattle, WA. We surveyed senior citizens' demographic background, health status, previous experiences, and beliefs about influenza and influenza vaccine. We determined the vaccination rates for influenza season 2001-2002 stratified by race, other sociodemographic factors, and attitudes toward influenza vaccination., Results: Surveys were mailed to 572 enrollees in SeniorCare Clinic. Three hundred twenty-four (57%) responded to the survey, 256 (79%) of whom reported receipt of influenza vaccination. Influenza vaccination rates did not vary significantly by race in this patient population: 80% for white persons, 70% for black persons, and 84% for Asians. Receipt of vaccination was associated with survey responses that indicated a discussion about the influenza shot with a health care provider and a positive attitude toward the influenza shot. History of side effects and negative attitude toward the influenza shot were associated with failure to receive the vaccine., Conclusions: In patients served by a university-affiliated geriatrics clinic, we found no statistically significant difference in influenza vaccination rate between white persons and other racial groups. Attitudes, beliefs, knowledge, and prior experiences toward the influenza shot were predictors of influenza vaccination. Physician recommendation and patient participation strongly correlated with vaccination acceptance.

The etiologic role of influenza in hospitalizations and deaths among persons infected with HIV since the introduction of highly active antiretroviral therapy (HAART) is not known. A retrospective cohort study was performed of all persons aged 15 to 50 years with AIDS or advanced HIV infection enrolled in the Tennessee Medicaid program from 1995 through 1999, representing 7368 person-years of follow-up. The influenza season was defined based on local virus surveillance, and hospitalizations were measured for acute cardiopulmonary causes and deaths from any cause throughout the year. From 1995 through 1999, cardiopulmonary hospitalization rates in HIV-infected patients declined by 53% and death rates declined by 77%. The influenza-attributable hospitalization rate was 48 (95% confidence interval [CI]: 16-91) per 1000 persons in 1995 and 5 (95% CI: -0.5-11) per 1000 persons per year during 1996 through 1999, after the introduction of HAART. Influenza-associated hospitalizations have declined in patients with HIV infection in the post-HAART era. Rates remain comparable to rates in other high-risk groups for which annual influenza vaccination is recommended, however.

To quantify health care use among adults during influenza and respiratory syncytial virus (RSV) seasons, we identified a cohort of veterans aged >or=18 years who used Department of Veterans Affairs (VA) facilities in Oregon and Washington states as their source of health care. During 1998-2000, veterans accrued 237,159 person-years of follow-up. Using VA data sources, we measured acute cardiopulmonary hospitalizations and primary care and urgent care visits. Differences between rates of study events when influenza and/or RSV were circulating and event rates when neither virus was circulating were used to calculate winter virus-attributable morbidity. Inpatient and outpatient event rates were consistently higher during winter virus season, compared with non-winter virus season. Annual rates of cardiopulmonary hospitalizations attributable to influenza or RSV infection ranged from 0.8 (95% confidence interval [CI], 0.1-1.5) per 1000 low-risk individuals aged 18-49 years, to 10.6 (95% CI, 7.5-13.6) per 1000 high-risk individuals aged >or=65 years. Each year, circulation of influenza and RSV coincide with predictable increases in medical care use.

We assessed whether trivalent live, cold-adapted influenza virus (CAIV-T) vaccine provides added protection when co-administered with trivalent inactivated influenza virus vaccine (TVV) in patients with chronic obstructive pulmonary disease (COPD). Subjects (N=2215) were randomly assigned to receive either TVV intramuscularly (IM) and CAIV-T intranasally (TC), or TVV and placebo (TP). The vaccines were well-tolerated. Efficacy of TC compared to TP was not statistically significant and was 0.16 for any influenza virus strain (95% confidence limit (CL): -0.22, 0.43), 0.26 for A (H3N2) virus (95% CL: -0.17, 0.53), and -0.05 for type B virus (95% CL: -1.13, 0.48). However, there was a possible advantage for TC over TP in reducing respiratory consequences of an influenza season measured by pulmonary function and symptoms at end of study.

A substudy analysis was conducted to determine the clinical characteristics associated with symptomatic, laboratory-documented influenza (LDI) among 2215 veterans with chronic obstructive pulmonary disease who participated in Department of Veterans Affairs Cooperative Study 448 and who received trivalent inactivated influenza virus vaccine with or without intranasal live-attenuated, cold-adapted influenza vaccine. Of 585 evaluable first occurrences of acute respiratory illnesses, 94 (16%) were LDI. Respiratory symptoms of cough, sputum production, and dyspnea occurred in >90% of patients with LDI; 68% had documented or subjective fever, and 81% had myalgias. Stepwise logistic regression identified only fever and myalgia as being statistically associated with LDI. During the influenza outbreak period, the positive predictive value of fever and myalgia was 41%. Clinical criteria were poor predictors of LDI in these older, vaccinated patients with chronic lung disease. Additional studies are warranted to define optimal methods for the diagnosis of influenza among older persons with chronic obstructive pulmonary disease.

Background: High attack rates of Influenzavirus among school-aged children tend to be expected to cause significant disruption of usual activities at school and at home., Objective: To quantify the effect of influenza season on illness episodes, school absenteeism, medication use, parental absenteeism from work, and the occurrence of secondary illness in families among a cohort of children enrolled in an elementary school during the 2000-2001 influenza season., Design: Prospective survey study., Setting: Kindergarten through eighth grade elementary school in Seattle, Wash., Patients or Other Participants: All children enrolled in the school were eligible for the study. Study participants were 313 children in 216 families., Main Outcome Measures: The primary outcome measure was missed school days. Secondary outcomes measures included total illness episodes, febrile illness episodes, medication usage, physician visits, parental workdays missed, and secondary illnesses among family members of children in the study cohort. Differences between the rates of study events among participants when influenza was circulating and the event rates during the winter season when influenza was not circulating were used to calculate influenza-attributable excess events., Results: Total illness episodes, febrile illness episodes, analgesic use, school absenteeism, parental industrial absenteeism, and secondary illness among family members were significantly higher during influenza season compared with the noninfluenza winter season. For every 100 children followed up for this influenza season, which included 37 school days, an excess 28 illness episodes and 63 missed school days occurred. Similarly, for every 100 children followed up, influenza accounted for an estimated 20 days of work missed by the parents and 22 secondary illness episodes among family members., Conclusion: Influenza season has significant adverse effects on the quality of life of school-aged children and their families.

Influenza is a common disease of childhood. Young children and children with high-risk medical conditions are at increased risk of being hospitalized when infected with influenza virus. Children of all ages have excess physician visits and receive excess antibiotic prescriptions during influenza season. The safety, immunogenicity, and efficacy of influenza vaccines in children are described in this review. Clinical trials and postlicensure experience have demonstrated that trivalent inactivated influenza vaccine is well-tolerated in children. Efficacy of the inactivated vaccine also has been demonstrated in numerous clinical trials. In comparison to trivalent inactivated influenza vaccine, investigational cold-adapted, live-attenuated influenza vaccine (LAIV) has the advantage of an intranasal route of administration. A large clinical trial demonstrated the tolerability and efficacy of the trivalent live, attenuated product in children 15 to 71 months of age. Pending information on safety and coadministration of this vaccine with other childhood vaccines will determine if it is licensed and recommended for use in children, including possible expanded indications for routine yearly administration to young children.

Many respiratory viruses cause morbidity in young children, but a licensed vaccine and effective oral therapy are available only for influenzavirus. To determine the incidence of laboratory-confirmed influenza illness, we prospectively followed up 1665 healthy children aged <5 years who were enrolled in the Vanderbilt Vaccine Clinic at some point from 1974 through 1999. Viral cultures were obtained when the children presented with clinical illness. The isolation of influenzavirus was associated with an estimated 95 health care visits for children with symptoms of influenza, 46 episodes of acute otitis media, and 8 episodes of lower respiratory tract disease per 1000 children yearly. Rates of acute otitis media and lower respiratory tract disease were highest among children aged <2 years. Hospitalizations associated with culture-positive influenza occurred at an annual rate of 3-4 per 1000 children aged <2 years. Influenza is associated with substantial morbidity in otherwise healthy children aged <5 years.

Background: Influenza is a common and potentially serious infection in children. Although there is interest in broadening the use of influenza vaccine in healthy children, there are few large, randomized, controlled trials that evaluate the safety and efficacy of inactivated vaccine in the pediatric population., Methods: From 1985 through 1990 a randomized, controlled trial of cold-adapted and inactivated vaccines for the prevention of influenza A disease was conducted at Vanderbilt University, and the cumulative results from this trial in patients of all ages have been previously published. We reanalyzed the data from this trial in the subset of patients who were younger than 16 years at the time of their participation. We determined vaccine safety, immunogenicity and efficacy, based on culture-positive illness and seroconversion, in this subset of patients., Results: During the 5 years of the study, 791 children younger than 16 years received 1809 doses of either inactivated or cold-adapted vaccine or placebo. The vaccines were well-tolerated, and there were no serious reactions. Inactivated trivalent influenza vaccines were 91.4 and 77.3% efficacious in preventing symptomatic, culture-positive influenza A H1N1 and H3N2 illness, respectively. The efficacy of the inactivated vaccine based on hemagglutination inhibition assay seroconversion was 67.1 and 65.5%, respectively, for H1N1 and H3N2 serotypes., Conclusions: Inactivated trivalent influenza A vaccines are well-tolerated and efficacious in the prevention of influenza A disease in children 1 to 16 years old.

Several recent developments offer opportunities to improve the diagnosis, treatment, and prevention of influenza. Rapid diagnostic tests assist in selecting patients for antiviral therapy and avoid some antibiotic use. The neuraminidase inhibitors now offer therapeutic options with potentially fewer side effects than the traditional drugs, albeit at greater cost. Inactivated influenza vaccine is now recommended annually for all persons aged 50 and older and younger adults and children (aged 6 months and older) who have underlying risk factors for the severe complications of influenza. This includes pregnant women who are in their second or third trimesters during influenza season.

Objective: Although influenza immunization is recommended for children with high-risk medical conditions, the majority of such children do not receive influenza vaccine. This study was designed to measure the burden of influenza among children with asthma and other chronic medical conditions., Study Design: We performed a retrospective cohort study of children younger than 15 years with medically treated asthma or other chronic medical conditions enrolled in the Tennessee Medicaid program from 1973 to 1993. We determined rates of hospitalization for acute cardiopulmonary disease, outpatient visits, and antibiotic courses throughout the year. Annual differences between event rates when influenza virus was circulating and event rates during winter months when there was no influenza in the community were used to calculate influenza-attributable morbidity., Results: Influenza accounted for an average of 19, 8, and 2 excess hospitalizations for cardiopulmonary disease yearly per 1000 high-risk children aged <1 year, 1 to <3 years, and 3 to <15 years, respectively. For every 1000 children, an estimated 120 to 200 outpatient visits and 65 to 140 antibiotic courses were attributable to influenza annually., Conclusions: Children younger than 15 years with asthma and other chronic medical conditions experience substantial morbidity requiring inpatient and outpatient care during influenza season. More effective targeting of this population for annual influenza immunization is warranted.

Antigen-specific mucosal immunity is thought to be important for protection against influenza virus infection. Currently licensed parenteral influenza vaccines stimulate the production of serum antibodies, but are poor inducers of mucosal immunity. The adjuvant MF59 has been shown to enhance the humoral immune response to parenteral influenza vaccine in humans and the mucosal immune response to intranasally-administered influenza vaccine in mice. We conducted an open-label safety study followed by an observer-blind, randomized trial comparing the immune response to intranasally-administered subunit influenza vaccine adjuvanted with MF59, unadjuvanted subunit influenza vaccine, and placebo. Adverse reactions did not occur significantly more frequently in vaccinees than placebo recipients. Of 31 subjects receiving 2 doses of MF59-adjuvanted influenza vaccine, 19 (61%), 8 (26%), and 11 (35%) developed a mucosal IgA response to influenza A/H1N1, A/H3N2, and B, respectively. The percentage of subjects with a serum antibody response was slightly lower. The immune responses to adjuvanted vaccine were not significantly different from those to unadjuvanted vaccine. Both vaccines gave more frequent responses than seen in placebo recipients, indicating the potential of intranasal inactivated vaccines to stimulate local IgA responses.

In the United States each year, influenza accounts for an estimated 20,000 to 40,000 deaths, nearly 300,000 hospitalizations, and millions of days lost from work. In the past few years, there has been an explosion of information in the medical literature related to influenza. This paper reviews these latest developments that enhance our understanding of influenza epidemiology and virology and expand our prevention and treatment options. Diminishing the impact of influenza in this country will require continued intense surveillance, increased use of influenza vaccine, and the availability of alternative vaccines and antivirals with the potential for broader protection against shift-and-drift strains of influenza.

Background: Despite high annual rates of influenza in children, influenza vaccines are given to children infrequently. We measured the disease burden of influenza in a large cohort of healthy children in the Tennessee Medicaid program who were younger than 15 years of age., Methods: We determined the rates of hospitalization for acute cardiopulmonary conditions, outpatient visits, and courses of antibiotics over a period of 19 consecutive years. Using the differences in the rates of these events when influenzavirus was circulating and the rates from November through April when there was no influenza in the community, we calculated morbidity attributable to influenza. There was a total of 2,035,143 person-years of observation., Results: During periods when influenzavirus was circulating, the average number of hospitalizations for cardiopulmonary conditions in excess of the expected number was 104 per 10,000 children per year for children younger than 6 months of age, 50 per 10,000 per year for those 6 months to less than 12 months, 19 per 10,000 per year for those 1 year to less than 3 years, 9 per 10,000 per year for those 3 years to less than 5 years, and 4 per 10,000 per year for those 5 years to less than 15 years. For every 100 children, an annual average of 6 to 15 outpatient visits and 3 to 9 courses of antibiotics were attributable to influenza. In winter, 10 to 30 percent of the excess number of courses of antibiotics occurred during periods when influenzavirus was circulating., Conclusions: Healthy children younger than one year of age are hospitalized for illness attributable to influenza at rates similar to those for adults at high risk for influenza. The rate of hospitalization decreases markedly with age. Influenza accounts for a substantial number of outpatient visits and courses of antibiotics in children of all ages.

Context: Data are limited on rates of influenza-associated hospitalizations and deaths among adults younger than 65 years., Objective: To quantify serious morbidity and mortality from influenza for women younger than 65 years with and without certain chronic medical conditions, including human immunodeficiency virus infection., Design: Retrospective cohort study., Setting and Population: Women aged 15 to 64 years enrolled in the Tennessee Medicaid program from 1974 to 1993., Main Outcome Measure: All hospitalizations for and deaths from pneumonia, influenza, and other selected acute cardiopulmonary conditions for women with and without selected chronic medical conditions during 19 consecutive years. Influenza-attributable risk was calculated by subtracting event rates during peri-influenza season (November through April of each year when influenza virus was not circulating) from adjusted rates during influenza season (November through April when influenza virus was circulating)., Results: During the 19 years of the study, we identified 53607 acute cardiopulmonary hospitalizations and deaths. Rates of such events were consistently higher during influenza seasons than peri-influenza seasons. Among high-risk women, the estimated annual excess was 23 hospitalizations and deaths per 10000 women aged 15 to 44 years and 58 such events per 10000 women aged 45 to 64 years. The estimated annual excess mortality due to influenza was 2 deaths per 10000 high-risk women for both age groups combined. Among women with no identified high-risk conditions, estimated annual excess hospitalizations and deaths were 4 and 6 per 10000 women aged 15 to 44 and 45 to 64 years, respectively., Conclusions: Women younger than 65 years with certain chronic medical conditions experience substantial morbidity and mortality from acute cardiopulmonary events during influenza season. More effective targeting of these populations for annual influenza immunization is warranted.

This study sought to quantify influenza-related serious morbidity in pregnant women, as measured by hospitalizations for or death from selected acute cardiopulmonary conditions during predefined influenza seasons. The study population included women aged 15-44 years who were enrolled in the Tennessee Medicaid program for at least 180 days between 1974 and 1993. In a nested case-control study, 4,369 women with a first study event during influenza season were compared with 21,845 population controls. The odds ratios associated with study events increased from 1.44 (95% confidence interval (CI) 0.97-2.15) for women at 14-20 weeks' gestation to 4.67 (95% CI 3.42-6.39) for those at 37-42 weeks in comparison with postpartum women. A retrospective cohort analysis, which controlled for risk factors identified in the case-control study, identified 22,824 study events during 1,393,166 women-years of follow-up. Women in their third trimester without other identified risk factors for influenza morbidity had an event rate of 21.7 per 10,000 women-months during influenza season. Approximately half of this morbidity, 10.5 (95% CI 6.7-14.3) events per 10,000 women-months, was attributable to influenza. Influenza-attributable risks in comparable nonpregnant and postpartum women were 1.91 (95% CI 1.51-2.31) and 1.16 (95% CI -0.09 to 2.42) per 10,000 women-months, respectively. The data suggest that, out of every 10,000 women in their third trimester without other identified risk factors who experience an average influenza season of 2.5 months, 25 will be hospitalized with influenza-related morbidity.

The development of a successful respiratory syncytial virus (RSV) vaccine will be advanced by an improved understanding of the pathogenesis of natural disease and vaccine-enhanced illness. Using a murine model, we have examined cytokine message expression and cytokine secretion in lungs of mice primed with killed or live antigens and challenged with RSV. Stable cytokine mRNA expression was achieved if the prime-challenge interval was 2 weeks. The pattern of expression of interleukin-4 (IL-4) and interferon-7 (IFN-gamma 1 mRNA was established by day 4 after challenge and was maintained at least through day 12, and was not affected by the concentration of priming immunogen or virus challenge. An enzyme-linked immunospot assay demonstrated that CD4+ T cells were responsible for the production of IL-4, while many cell types secreted IFN-gamma. These experiments begin to define the kinetics of cytokine expression and phenotypes of cytokine-producing cells following RSV infection, supporting previous findings that suggested aberrant infiltration of CD4+ T lymphocytes and excessive IL-4 secretion may play a role in the vaccine-enhanced disease associated with RSV.

The ability of monophosphoryl lipid A (MPL), QS-21 and alum to alter the immunologic response to immunization with respiratory syncytial virus a chimeric FG construct (FG) subunit vaccine was examined in BALB/c mice. FG/MPL, FG/alum, and FG/MPL/QS-21 combinations increased non-neutralizing antibody response, while FG/QS-21 did not. FG subunit vaccine with MPL, QS-21, or both had cytokine responses more closely resembling primary infection than FG/alum, with decreased interleukin-4 mRNA levels and increased IgG2a isotype antibody. The lungs of the mice immunized with FG subunit vaccines showed a heightened inflammatory response to respiratory syncytial virus challenge as compared to live virus immunization. Adjuvants can be used to alter the humoral and cellular responses to RSV subunit immunization.

Respiratory syncytial virus (RSV) infection causes substantial morbidity in young children and immunocompromised adults, yet its pathogenesis is poorly understood. Because the proinflammatory cytokine tumor necrosis factor-alpha (TNF-alpha) may be important in host response to viral infection, HEp-2 cells were treated with TNF-alpha and mice were given TNF-alpha antibody before RSV infection. Pretreatment of HEp-2 cells with TNF-alpha inhibited RSV replication as determined by cytopathic effect. Respiratory syncytial virus-infected BALB/c mice treated with antibody to TNF-alpha had greater maximal weight loss and slower recovery time than control mice. These results suggest a protective role for TNF-alpha in RSV infection.

Infants with respiratory syncytial virus infection have low serum vitamin A levels. We treated 21 respiratory syncytial virus-infected children with 12,500 to 25,000 IU of oral vitamin A. Vitamin A levels were normalized at 6 h, and none of the children experienced vitamin A toxicity or exacerbation of respiratory illness. Vitamin A treatment of previously healthy respiratory syncytial virus-infected infants at these doses is safe and well tolerated.

A case of blastomycosis is reported involving the mediastinum and compromising the plexus brachialis. The pathology, pathophysiology, and treatment of this patient and of a previously reported patient are discussed and compared with the characteristics of extrapulmonary thoracic disease caused by histoplasmosis. Because of the favorable response of these patients to prolonged antifungal therapy, blastomycosis should be considered in the differential diagnosis of invasive extrapulmonary thoracic disease.

Campylobacter fetus causes systemic infections in immunocompromised hosts. We describe a case in which C. fetus bacteremia apparently relapsed after 7 years in a patient with hypogammaglobulinemia and characterize the serum resistance of the patient's C. fetus strain and the inability of the patient's serum, with and without commercial intravenous immunoglobulin, to opsonize this and another C. fetus strain effectively. The probable presence of a sequestered site of infection in bone, the intrinsic serum resistance of the C. fetus strain, and the absence of specific antibody may account for the persistent infection in this patient. These studies suggest that intravenous immunoglobulin treatment is not useful in eradicating C. fetus bacteremia.

Respiratory syncytial virus causes worldwide epidemics of respiratory disease. Of 23 children infected with respiratory syncytial virus, 65% had low serum concentrations of vitamin A during acute illness; these low values were associated with more severe illness. Vitamin A supplementation may have a role in the management of infection with respiratory syncytial virus.

Defining the mechanism for the vaccine-enhanced illness associated with respiratory syncytial virus (RSV) is critical for advancing RSV vaccine development. Previous studies in which infants were vaccinated with formalin-inactivated alum-precipitated whole virus did not protect from RSV infection, and those infected had a high incidence of severe illness. In contrast, previous clinical trials evaluating live attenuated RSV showed no associated vaccine-enhanced illness. We have used a mouse model to explore the immunopathogenesis of RSV infection. In this study cytokine mRNA expression was examined using 32P-labeled oligonucleotide probes in Northern blot analyses of polyA RNA extracted from lungs of mice primed with various vaccine preparations then challenged nasally with live RSV. We have shown that upon challenge, priming of mice with inactivated virus or subunit F glycoprotein induced a pattern of cytokine mRNA expression suggesting a dominant Th2-like lymphocyte response (relative increase in IL-4 mRNA expression). In contrast, challenge of mice primed with live RSV by parenteral or mucosal routes induced a Th1-like pattern of cytokine mRNA expression (relative decrease in IL-4 mRNA expression compared to IFN-gamma mRNA expression). Thus, the formulation and route of delivery of vaccine products can influence the pattern of cytokine expression in lung upon RSV challenge.