Kathleen M. Neuzil

THE EFFECT OF INFLUENZA ON HOSPITALIZATIONS, OUTPATIENT VISITS, AND COURSES OF ANTIBIOTICS IN CHILDREN

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.

Effect of Human Rotavirus Vaccine on Severe Diarrhea in African Infants

BACKGROUND Rotavirus is the most common cause of severe gastroenteritis among young children worldwide. Data are needed to assess the efficacy of the rotavirus vaccine in African children. METHODS We conducted a randomized, placebo-controlled, multicenter trial in South Africa (3166 infants; 64.1% of the total) and Malawi (1773 infants; 35.9% of the total) to evaluate the efficacy of a live, oral rotavirus vaccine in preventing severe rotavirus gastroenteritis. Healthy infants were randomly assigned in a 1:1:1 ratio to receive two doses of vaccine (in addition to one dose of placebo) or three doses of vaccine--the pooled vaccine group--or three doses of placebo at 6, 10, and 14 weeks of age. Episodes of gastroenteritis caused by wild-type rotavirus during the first year of life were assessed through active follow-up surveillance and were graded with the use of the Vesikari scale. RESULTS A total of 4939 infants were enrolled and randomly assigned to one of the three groups; 1647 infants received two doses of the vaccine, 1651 infants received three doses of the vaccine, and 1641 received placebo. Of the 4417 infants included in the per-protocol efficacy analysis, severe rotavirus gastroenteritis occurred in 4.9% of the infants in the placebo group and in 1.9% of those in the pooled vaccine group (vaccine efficacy, 61.2%; 95% confidence interval, 44.0 to 73.2). Vaccine efficacy was lower in Malawi than in South Africa (49.4% vs. 76.9%); however, the number of episodes of severe rotavirus gastroenteritis that were prevented was greater in Malawi than in South Africa (6.7 vs. 4.2 cases prevented per 100 infants vaccinated per year). Efficacy against all-cause severe gastroenteritis was 30.2%. At least one serious adverse event was reported in 9.7% of the infants in the pooled vaccine group and in 11.5% of the infants in the placebo group. CONCLUSIONS Human rotavirus vaccine significantly reduced the incidence of severe rotavirus gastroenteritis among African infants during the first year of life. (ClinicalTrials.gov number, NCT00241644.)

Efficacy of pentavalent rotavirus vaccine against severe rotavirus gastroenteritis in infants in developing countries in Asia: a randomised, double-blind, placebo-controlled trial

BACKGROUND Rotavirus vaccine has proved effective for prevention of severe rotavirus gastroenteritis in infants in developed countries, but no efficacy studies have been done in developing countries in Asia. We assessed the clinical efficacy of live oral pentavalent rotavirus vaccine for prevention of severe rotavirus gastroenteritis in infants in Bangladesh and Vietnam. METHODS In this multicentre, double-blind, placebo-controlled trial, undertaken in rural Matlab, Bangladesh, and urban and periurban Nha Trang, Vietnam, infants aged 4-12 weeks without symptoms of gastrointestinal disorders were randomly assigned (1:1) to receive three oral doses of pentavalent rotavirus vaccine 2 mL or placebo at around 6 weeks, 10 weeks, and 14 weeks of age, in conjunction with routine infant vaccines including oral poliovirus vaccine. Randomisation was done by computer-generated randomisation sequence in blocks of six. Episodes of gastroenteritis in infants who presented to study medical facilities were reported by clinical staff and from parent recollection. The primary endpoint was severe rotavirus gastroenteritis (Vesikari score >or=11) arising 14 days or more after the third dose of placebo or vaccine to end of study (March 31, 2009; around 21 months of age). Analysis was per protocol; infants who received scheduled doses of vaccine or placebo without intervening laboratory-confirmed naturally occurring rotavirus disease earlier than 14 days after the third dose and had complete clinical and laboratory results were included in the analysis. This study is registered with ClinicalTrials.gov, number NCT00362648. FINDINGS 2036 infants were randomly assigned to receive pentavalent rotavirus vaccine (n=1018) or placebo (n=1018). 991 infants assigned to pentavalent rotavirus vaccine and 978 assigned to placebo were included in the per-protocol analysis. Median follow up from 14 days after the third dose of placebo or vaccine until final disposition was 498 days (IQR 480-575). 38 cases of severe rotavirus gastroenteritis (Vesikari score >or=11) were reported during more than 1197 person-years of follow up in the vaccine group, compared with 71 cases in more than 1156 person years in the placebo group, resulting in a vaccine efficacy of 48.3% (95% CI 22.3-66.1) against severe disease (p=0.0005 for efficacy >0%) during nearly 2 years of follow-up. 25 (2.5%) of 1017 infants assigned to receive vaccine and 20 (2.0%) of 1018 assigned to receive placebo had a serious adverse event within 14 days of any dose. The most frequent serious adverse event was pneumonia (vaccine 12 [1.2%]; placebo 15 [1.5%]). INTERPRETATION In infants in developing countries in Asia, pentavalent rotavirus vaccine is safe and efficacious against severe rotavirus gastroenteritis, and our results support expanded WHO recommendations to promote its global use. FUNDING PATH (GAVI Alliance grant) and Merck.

Seasonal Influenza in Adults and Children—Diagnosis, Treatment, Chemoprophylaxis, and Institutional Outbreak Management: Clinical Practice Guidelines of the Infectious Diseases Society of America

Guidelines for the treatment of persons with influenza virus infection were prepared by an Expert Panel of the Infectious Diseases Society of America. The evidence-based guidelines encompass diagnostic issues, treatment and chemoprophylaxis with antiviral medications, and issues related to institutional outbreak management for seasonal (interpandemic) influenza. They are intended for use by physicians in all medical specialties with direct patient care, because influenza virus infection is common in communities during influenza season and may be encountered by practitioners caring for a wide variety of patients.

Burden of Interpandemic Influenza in Children Younger than 5 Years: A 25-Year Prospective Study

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.

The burden of community-acquired pneumonia in seniors: results of a population-based study.

Abstract 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 ⩾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 ⩾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 ∼1 of every 20 persons aged ⩾85 years will have a new episode of community-acquired pneumonia each year.

Influenza estacional en adultos y niños—Diagnóstico, tratamiento, quimioprofilaxis y control de brotes institucionales: Guías de práctica clínica de la Sociedad de Enfermedades Infecciosas de Estados Unidos de América

Abstract Un Grupo de Expertos de la Sociedad de Enfermedades Infecciosas de los Estados Unidos de América elaboró las guias para el tratamiento de personas infectadas por el virus de la influenza. Estas guias basadas en datos y pruebas cientificas comprenden el diagnóstico, el tratamiento y la quimioprofilaxis con medicamentos antivirales, además de temas relacionados con el control de brotes de influenza estacional (interpandémicas) en ámbitos institucionales. Están destinadas a los médicos de todas las especialidades a cargo de la atención directa de pacientes porque los médicos generales que atienden una gran variedad de casos son los que se enfrentan con la influenza, frecuente en el ámbito comunitario durante la temporada de influenza.

Maternal morbidity and perinatal outcomes among pregnant women with respiratory hospitalizations during influenza season

OBJECTIVES A population-based assessment of maternal and perinatal morbidity related to respiratory illness during influenza season among pregnant women has not been published. The objectives of this investigation were to describe and quantify the impact of respiratory hospitalization during pregnancy on serious maternal and perinatal morbidity. STUDY DESIGN A matched cohort study using an administrative database of pregnant women enrolled in the Tennessee Medicaid population to determine pregnancy outcomes associated with respiratory hospitalizations during influenza season. Pregnant women aged 15 to 44 years with a respiratory hospitalization during influenza seasons 1985-1993 were matched by gestational age and presence of comorbidity with pregnant control subjects without a respiratory hospitalization. RESULTS During the eight influenza seasons studied, 293 women with singleton pregnancies had respiratory disease hospitalizations (5.1:1000). Women with asthma had high rates of such hospitalization (59.7:1000). Compared with matched controls, women with respiratory hospitalizations had similar modes of delivery, delivery length of stay, and episodes of preterm labor. The prevalence of prematurity and low birth weight among infants born to such women was likewise similar between the two groups. CONCLUSION In this population of pregnant women, those with asthma accounted for half of all respiratory-related hospitalizations during influenza seasons, with 6% of pregnant women with asthma requiring respiratory hospitalization during influenza season, (odds ratio 10.63, 95% CI, 8.18-13.83, compared with women without a medical comorbidity). We detected no significant increase in adverse perinatal outcomes associated with respiratory hospitalizations during influenza season.

Influenza vaccination of pregnant women and protection of their infants.

BACKGROUND There are limited data on the efficacy of vaccination against confirmed influenza in pregnant women with and those without human immunodeficiency virus (HIV) infection and protection of their infants. METHODS We conducted two double-blind, randomized, placebo-controlled trials of trivalent inactivated influenza vaccine (IIV3) in South Africa during 2011 in pregnant women infected with HIV and during 2011 and 2012 in pregnant women who were not infected. The immunogenicity, safety, and efficacy of IIV3 in pregnant women and their infants were evaluated until 24 weeks after birth. Immune responses were measured with a hemagglutination inhibition (HAI) assay, and influenza was diagnosed by means of reverse-transcriptase-polymerase-chain-reaction (RT-PCR) assays of respiratory samples. RESULTS The study cohorts included 2116 pregnant women who were not infected with HIV and 194 pregnant women who were infected with HIV. At 1 month after vaccination, seroconversion rates and the proportion of participants with HAI titers of 1:40 or more were higher among IIV3 recipients than among placebo recipients in both cohorts. Newborns of IIV3 recipients also had higher HAI titers than newborns of placebo recipients. The attack rate for RT-PCR-confirmed influenza among both HIV-uninfected placebo recipients and their infants was 3.6%. The attack rates among HIV-uninfected IIV3 recipients and their infants were 1.8% and 1.9%, respectively, and the respective vaccine-efficacy rates were 50.4% (95% confidence interval [CI], 14.5 to 71.2) and 48.8% (95% CI, 11.6 to 70.4). Among HIV-infected women, the attack rate for placebo recipients was 17.0% and the rate for IIV3 recipients was 7.0%; the vaccine-efficacy rate for these IIV3 recipients was 57.7% (95% CI, 0.2 to 82.1). CONCLUSIONS Influenza vaccine was immunogenic in HIV-uninfected and HIV-infected pregnant women and provided partial protection against confirmed influenza in both groups of women and in infants who were not exposed to HIV. (Funded by the Bill and Melinda Gates Foundation and others; ClinicalTrials.gov numbers, NCT01306669 and NCT01306682.).

Efficacy of inactivated and cold-adapted vaccines against influenza A infection, 1985 to 1990: the pediatric experience.

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.