Differentiating severe and non-severe lower respiratory tract illness in patients hospitalized with influenza: Development of the Influenza Disease Evaluation and Assessment of Severity (IDEAS) scale.

BACKGROUND: Experimental studies have shown that vaccination can reduce viral replication to attenuate progression of influenza-associated lower respiratory tract illness (LRTI). However, clinical studies are conflicting, possibly due to use of non-specific outcomes reflecting a mix of large and small airway LRTI lacking specificity for acute lung or organ injury. METHODS: We developed a global ordinal scale to differentiate large and small airway LRTI in hospitalized adults with influenza using physiologic features and interventions (PFIs): vital signs, laboratory and radiographic findings, and clinical interventions. We reviewed the literature to identify common PFIs across 9 existing scales of pneumonia and sepsis severity. To characterize patients using this scale, we applied the scale to an antiviral clinical trial dataset where these PFIs were measured through routine clinical care in adults hospitalized with influenza-associated LRTI during the 2010-2013 seasons. RESULTS: We evaluated 12 clinical parameters among 1020 adults; 210 (21%) had laboratory-confirmed influenza, with a median severity score of 4.5 (interquartile range, 2-8). Among influenza cases, median age was 63 years, 20% were hospitalized in the prior 90 days, 50% had chronic obstructive pulmonary disease, and 22% had congestive heart failure. Primary influencers of higher score included pulmonary infiltrates on imaging (48.1%), heart rate ≥110 beats/minute (41.4%), oxygen saturation <93% (47.6%) and respiratory rate >24 breaths/minute (21.0%). Key PFIs distinguishing patients with severity < or ≥8 (upper quartile) included infiltrates (27.1% vs 90.0%), temperature ≥ 39.1°C or <36.0°C (7.1% vs 27.1%), respiratory rate >24 breaths/minute (7.9% vs 47.1%), heart rate ≥110 beats/minute (29.3% vs 65.7%), oxygen saturation <90% (14.3% vs 31.4%), white blood cell count >15,000 (5.0% vs 27.2%), and need for invasive or non-invasive mechanical ventilation (2.1% vs 15.7%). CONCLUSION: We developed a scale in adults hospitalized with influenza-associated LRTI demonstrating a broad distribution of physiologic severity which may be useful for future studies evaluating the disease attenuating effects of influenza vaccination or other therapeutics.

Use of Patients With Diarrhea Who Test Negative for Rotavirus as Controls to Estimate Rotavirus Vaccine Effectiveness Through Case-Control Studies.

BACKGROUND: Case-control studies are often performed to estimate postlicensure vaccine effectiveness (VE), but the enrollment of controls can be challenging, time-consuming, and costly. We evaluated whether children enrolled in the same hospital-based diarrheal surveillance used to identify rotavirus cases but who test negative for rotavirus (test-negative controls) can be considered a suitable alternative to nondiarrheal hospital or community-based control groups (traditional controls). METHODS: We compared calculated VE estimates as a function of varying values of true VE, attack rates of rotavirus and nonrotavirus diarrhea in the population, and sensitivity and specificity of the rotavirus enzyme immunoasssay. We also searched the literature to identify rotavirus VE studies that used traditional and test-negative control groups and compared VE estimates obtained using the different control groups. RESULTS: Assuming a 1% attack rate for severe rotavirus diarrhea, a 3% attack rate for severe nonrotavirus diarrhea in the population, a test sensitivity of 96%, and a specificity of 100%, the calculated VE estimates using both the traditional and test-negative control groups closely approximated the true VE for all values from 30% to 100%. As true VE decreased, the traditional case-control approach slightly overestimated the true VE and the test-negative case-control approach slightly underestimated this estimate, but the absolute difference was only ±0.2 percentage points. Field VE estimates from 10 evaluations that used both traditional and test-negative control groups were similar regardless of control group used. CONCLUSIONS: The use of rotavirus test-negative controls offers an efficient and cost-effective approach to estimating rotavirus VE through case-control studies.

Impact of rotavirus vaccination on diarrhea-related hospitalizations in São Paulo State, Brazil.

INTRODUCTION: Following introduction of routine infant rotavirus vaccination, severe diarrhea hospitalization rates declined among children aged <5 years throughout Brazil. Ensuring equity of rotavirus vaccine impact is important in countries that self-finance immunization programs. The objective of this study was to examine rotavirus vaccine impact on diarrhea admission rates among children aged <5 years in Brazil's public health system, according to area-based measures of human development in the state of São Paulo, Brazil. METHODS: Ecological analysis of public health system hospitalization rates for acute gastroenteritis among children aged <5 years in the state of São Paulo, Brazil, according to five categories of municipal development based on a modified Human Development Index for municipalities. Acute gastroenteritis hospitalization rates among children aged <5 years after national rotavirus vaccine introduction (2008-2011) were compared to rates in pre-vaccine years (2000-2005) to calculate percent decline in rates (1-rate ratio) and 95% confidence intervals (CI) for each municipal development category. Direct hospitalization costs during the two periods were compared. RESULTS: Annual rates declined by 40% (95% CI, 39-42%) from 631 diarrhea hospitalizations per 100,000 person years pre-rotavirus vaccination to 377 per 100,000 post-vaccination among children aged <5 years and 50% (95% CI, 48-52%) from 1009 to 505 per 100,000 among infants. Highest rates were observed in least developed municipalities. Significant declines of 26-52% among children <5 years and 41-63% among infants were observed in all categories of municipal development. Lower diarrhea hospitalization rates resulted in annual savings of approximately 2 million USD for the state of São Paulo. Savings in direct hospitalization costs benefitted municipalities in all five categories. CONCLUSION: The introduction of rotavirus vaccination was associated with substantial reductions of diarrhea-related admissions at all levels of municipal development in São Paulo State, Brazil.

Potential intussusception risk versus benefits of rotavirus vaccination in the United States.

BACKGROUND: International data show a low-level increased risk of intussusception associated with rotavirus vaccination. Although US data have not documented a risk, we assumed a risk similar to international settings and compared potential vaccine-associated intussusception cases with benefits of prevention of rotavirus gastroenteritis by a fully implemented US rotavirus vaccine program. METHODS: To calculate excess intussusception cases, we used national data on vaccine coverage and baseline intussusception rates, and assumed a vaccine-associated intussusception relative risk of 5.3 (95% confidence interval [CI]: 3.0-9.3) in the first week after the first vaccine dose, the risk seen in international settings. We used postlicensure vaccine effectiveness data to calculate rotavirus disease burden averted. RESULTS: For a US birth cohort of 4.3 million infants, vaccine-associated intussusception could cause an excess 0.2 (range: 0.1-0.3) deaths, 45 (range: 21-86) hospitalizations and 13 (range: 6-25) cases managed in short-stay or emergency department settings. Vaccination would avert 14 (95% CI: 10-19) rotavirus-associated deaths, 53,444 (95% CI: 37,622-72,882) hospitalizations and 169,949 (95% CI: 118,161-238,630) emergency department visits. Summary benefit-risk ratios for death and hospitalization are 71:1 and 1093:1, respectively. CONCLUSIONS: The burden of severe rotavirus disease averted due to vaccination compared with the vaccine-associated intussusception events offers a side-by-side analysis of the benefits and potential risks. If an intussusception risk similar to that seen internationally exists in the United States, it is substantially exceeded by the benefits of rotavirus disease burden averted by vaccination.

Post-licensure experience with rotavirus vaccination in high and middle income countries; 2006 to 2011.

Rotavirus causes one-third to one-half of severe diarrheal disease in children under the age of five years worldwide. In 2006 two rotavirus vaccines became available and, in the intervening years, approximately thirty countries have introduced them into their immunization programs, primarily in high-income and middle-income settings. Major reductions in rotavirus hospitalizations have been observed in a number of these locations, and in select countries, there have been impacts on gastroenteritis mortality associated with rotavirus vaccine introduction. In addition to these direct health benefits, reduced gastroenteritis risk has been documented in unvaccinated groups, including older children and adults, suggesting indirect benefits (i.e. herd immunity). In this paper, we summarize what has been learned from programs studying post-licensure vaccine effectiveness, impact on health-care utilization and death, safety issues (namely, intussception and the detection of adventitious viruses) and the potential selective pressure of vaccination on the diversity of rotavirus genotypes.

All-cause gastroenteritis and rotavirus-coded hospitalizations among US children, 2000-2009.

BACKGROUND: Rotavirus vaccine was recommended for US infants in 2006. We estimated baseline prevaccine burden and monitored postvaccine trends in gastroenteritis-coded and rotavirus-coded hospitalizations among US children. METHODS: We analyzed data from the State Inpatient Databases (SID) for 29-44 US states over a 10-year period (2000-2009) to calculate gastroenteritis and rotavirus-coded hospitalization rates by age group, sex, and region, among children <5 years of age. By extrapolating observed pre- and postvaccine gastroenteritis hospitalization rates to the US population <5 years and based on the 2009 cost of a diarrhea hospitalization, we estimated national reductions in diarrhea hospitalizations and associated treatment costs. RESULTS: The prevaccine (2000-2006) annual average gastroenteritis-coded hospitalization rate among children <5 years of age was 74 per 10,000 (annual range, 71-82 per 10,000), and declined to 51 and 50 per 10,000 in 2008 and 2009, respectively (P < .001). The prevaccine (2000-2006) annual average rotavirus-coded hospitalization rate among children <5 years of age was 15 per 10,000 (annual range, 13-18 per 10,000), and declined to 5 and 6 per 10,000 in 2008 and 2009, respectively (P < .001). The decreases in rotavirus-coded hospitalization rates in 2008 and 2009 compared with rates in prevaccine years were observed among all age groups and US regions. Nationally, during 2008 and 2009 combined, we estimated a reduction of approximately 77,000 diarrhea hospitalizations and approximately $242 million in hospital costs. CONCLUSIONS: Since implementation of the US rotavirus vaccination program, a marked reduction in diarrhea hospitalizations and related hospital charges has occurred among US children.

Potential intussusception risk versus health benefits from rotavirus vaccination in Latin America.

BACKGROUND: With the recent postlicensure identification of an increased risk of intussusception with rotavirus vaccine, the 14 Latin American countries currently using rotavirus vaccine must now weigh the health benefits versus risks to assess whether to continue vaccination. To inform policy considerations, we estimated excess intussusception cases and mortality potentially caused by rotavirus vaccine for each of the 14 countries and compared these estimates to hospitalizations and deaths expected to be averted through vaccination. METHODS: We used regional rotavirus disease burden and rotavirus vaccine efficacy data, global natural intussusception and regional rotavirus vaccine-related risk estimates, and country-specific diphtheria, tetanus, and pertussus vaccination coverage rates to estimate rotavirus vaccine coverage rates. We performed a probabilistic sensitivity analysis to account for uncertainty in these parameters. RESULTS: For an aggregate hypothetical birth cohort of 9.5 million infants in these 14 countries, rotavirus vaccine would annually prevent 144 746 (90% confidence interval [CI], 128 821-156 707) hospitalizations and 4124 deaths (90% CI, 3740-4239) due to rotavirus in their first 5 years of life but could cause an additional 172 hospitalizations (90% CI, 126-293) and 10 deaths (90% CI, 6-17) due to intussusception, yielding benefit-risk ratios for hospitalization and death of 841:1 (90% CI, 479:1 to 1142:1) and 395:1 (90% CI, 207:1 to 526:1), respectively. In an uncertainty analysis using 10 000 simulations of our probabilistic parameters, in comparing rotavirus disease averted to intussusception events caused, the hospitalization ratio was never below 100:1, and our death ratio fell below 100:1 only once. CONCLUSIONS: The health benefits of vaccination far outweigh the short-term risks and support continued rotavirus vaccination in Latin America.

Remaining issues and challenges for rotavirus vaccine in preventing global childhood diarrheal morbidity and mortality.

Rotavirus vaccines have had a dramatic impact on morbidity and mortality from diarrhea among children in high- and middle-income countries that have introduced the vaccine into their national immunization programs. Widespread introduction of rotavirus vaccine in developing countries is imminent and their full potential in reducing the global burden from severe childhood diarrhea may soon be realized. The objectives of this paper are to describe the remaining issues and challenges in ensuring the success of the global rotavirus vaccination program and to discuss further research needed to help address them.

Rotavirus vaccine and health care utilization for diarrhea in U.S. children.

BACKGROUND: Routine vaccination of U.S. infants with pentavalent rotavirus vaccine (RV5) began in 2006. METHODS: Using MarketScan databases, we assessed RV5 coverage and diarrhea-associated health care use from July 2007 through June 2009 versus July 2001 through June 2006 in children under 5 years of age. We compared the rates of diarrhea-associated health care use in unvaccinated children in the period from January through June (when rotavirus is most prevalent) in 2008 and 2009 with the prevaccine rates to estimate indirect benefits. We estimated national reductions in the number of hospitalizations for diarrhea, and associated costs, by extrapolation. RESULTS: By December 31, 2008, at least one dose of RV5 had been administered in 73% of children under 1 year of age, 64% of children 1 year of age, and 8% of children 2 to 4 years of age. Among children under 5 years of age, rates of hospitalization for diarrhea in 2001-2006, 2007-2008, and 2008-2009 were 52, 35, and 39 cases per 10,000 person-years, respectively, for relative reductions from 2001-2006 by 33% (95% confidence interval [CI], 31 to 35) in 2007-2008 and by 25% (95% CI, 23 to 27) in 2008-2009; rates of hospitalization specifically coded for rotavirus infection were 14, 4, and 6 cases per 10,000 person-years, respectively, for relative reductions in the rate from 2001-2006 by 75% (95% CI, 72 to 77) in 2007-2008 and by 60% (95% CI, 58 to 63) in 2008-2009. In the January-June periods of 2008 and 2009, the respective relative rate reductions among vaccinated children as compared with unvaccinated children were as follows: hospitalization for diarrhea, 44% (95% CI, 33 to 53) and 58% (95% CI, 52 to 64); rotavirus-coded hospitalization, 89% (95% CI, 79 to 94) and 89% (95% CI, 84 to 93); emergency department visits for diarrhea, 37% (95% CI, 31 to 43) and 48% (95% CI, 44 to 51); and outpatient visits for diarrhea, 9% (95% CI, 6 to 11) and 12% (95% CI, 10 to 15). Indirect benefits (in unvaccinated children) were seen in 2007-2008 but not in 2008-2009. Nationally, for the 2007-2009 period, there was an estimated reduction of 64,855 hospitalizations, saving approximately $278 million in treatment costs. CONCLUSIONS: Since the introduction of rotavirus vaccine, diarrhea-associated health care utilization and medical expenditures for U.S. children have decreased substantially.

Sociodemographic and dietary risk factors for natural infant intussusception in the United States.

BACKGROUND: In 1999, a US case-control study demonstrated a strong association between intussusception and a rotavirus vaccine (Rotashield). However, because most (87%) cases were not temporally associated with vaccination, we reanalyzed these data to assess risk factors for intussusception cases unrelated to Rotashield. PATIENTS AND METHODS: Case-patients were infants with intussusception between November 1998 and June 1999. Controls were matched by age and hospital of birth. Sociodemographic and feeding practice data were collected through parent and provider interviews. Conditional logistic regression was used to identify risk factors for intussusception, controlling for exposure to Rotashield <21 days before intussusception. RESULTS: Four hundred twenty-nine cases and 1763 controls were enrolled. Among case-patients, 372 (87%) had not received Rotashield within 21 days before intussusception. After adjusting for recent Rotashield administration, factors associated with intussusception included male sex (odds ratio [OR] 1.7; 95% confidence interval [CI] 1.3-2.2), Hispanic (OR 2.1; 95% CI 1.4-3.2) or black (OR 1.8; 95% CI 1.2-2.7) race/ethnicity, and Medicaid enrollment (OR 1.5; 95% CI 1.1-2.0). Feeding practices modified the risk of intussusception. Interaction was found between introduction of solid food (ISF) and type of formula consumption. Using breast milk as the referent group, infants with ISF for at least 5 weeks who consumed soy milk-based formula had a lower risk (OR 0.26; 95% CI 0.1-0.7) and infants without ISF who consumed cow's-milk formula had an increased risk (OR 2.33; 95% CI 1.4-3.9). CONCLUSIONS: Risk of intussusception among US infants varies based on sociodemographic characteristics and feeding patterns.

Assessing the effectiveness and public health impact of rotavirus vaccines after introduction in immunization programs.

Two new vaccines against severe rotavirus gastroenteritis that have high efficacy in middle- and high-income countries have recently been licensed in many countries worldwide. Clinical trials in low-income countries in Africa and Asia are ongoing. Experience gained through studies of natural rotavirus infection and the clinical trials for the current and previous rotavirus vaccines indicate that, as countries begin to introduce these newly approved vaccines into routine childhood immunization programs, monitoring their performance in real world settings should be a high priority. Key epidemiological considerations in the postlicensure period include (1) how the vaccine will perform against severe rotavirus disease under routine public health use; (2) how routine vaccination will impact the epidemiology of disease with regard to the burden of severe disease and death, age distribution of cases, seasonality, and serotype distribution; (3) whether vaccination will have a sufficient impact on transmission to reduce disease burden in unvaccinated age groups; and (4) whether vaccine will confer protection through the first 3 years of life, when most severe disease and mortality associated with rotavirus occur. Monitoring of impact with focus on these public health considerations will allow parents, health care providers, and decision makers to appreciate the health benefits of vaccination in reducing the burden of severe rotavirus disease. It will also allow assessment of the effectiveness of rotavirus vaccines in programmatic use and the need for modifying vaccination schedules or vaccine formulations to enhance the performance of immunization. In this article, we review data for the protective efficacy of the 2 new rotavirus vaccines, with emphasis on issues particularly important for consideration as these vaccines are introduced in routine infant immunization programs.

A qualitative assessment of factors influencing acceptance of a new rotavirus vaccine among health care providers and consumers.

BACKGROUND: In 2006, a new rotavirus vaccine (RotaTeq) was licensed in the US and recommended for routine immunization of all US infants. Because a previously licensed vaccine (Rotashield) was withdrawn from the US for safety concerns, identifying barriers to uptake of RotaTeq will help develop strategies to broaden vaccine coverage. METHODS: We explored beliefs and attitudes of parents (n = 57) and providers (n = 10) towards rotavirus disease and vaccines through a qualitative assessment using focus groups and in-depth interviews. RESULTS: All physicians were familiar with safety concerns about rotavirus vaccines, but felt reassured by RotaTeq's safety profile. When asked about likelihood of using RotaTeq on a scale of one to seven (1 = "absolutely not;" 7 = "absolutely yes") the mean score was 5 (range = 3-6). Physicians expressed a high likelihood of adopting RotaTeq, particularly if recommended by their professional organizations and expressed specific interest in post-marketing safety data. Similarly, consumers found the RotaTeq safety profile to be favorable and would rely on their physician's recommendation for vaccination. However, when asked to rank likelihood of having their child vaccinated against rotavirus (1 = "definitely not get;" 7 = "definitely get"), 29% ranked 1 or 2, 36% 3 or 4, and 35% 5 to 7. CONCLUSION: Our qualitative assessment provides complementary data to recent quantitative surveys and suggests that physicians and parents are likely to adopt the newly licensed rotavirus vaccine. Increasing parental awareness of the rotavirus disease burden and providing physicians with timely post-marketing surveillance data will be integral to a successful vaccination program.