Global, regional, and national disease burden estimates of acute lower respiratory infections due to respiratory syncytial virus in young children in 2015: a systematic review and modelling study.

BACKGROUND: We have previously estimated that respiratory syncytial virus (RSV) was associated with 22% of all episodes of (severe) acute lower respiratory infection (ALRI) resulting in 55 000 to 199 000 deaths in children younger than 5 years in 2005. In the past 5 years, major research activity on RSV has yielded substantial new data from developing countries. With a considerably expanded dataset from a large international collaboration, we aimed to estimate the global incidence, hospital admission rate, and mortality from RSV-ALRI episodes in young children in 2015. METHODS: We estimated the incidence and hospital admission rate of RSV-associated ALRI (RSV-ALRI) in children younger than 5 years stratified by age and World Bank income regions from a systematic review of studies published between Jan 1, 1995, and Dec 31, 2016, and unpublished data from 76 high quality population-based studies. We estimated the RSV-ALRI incidence for 132 developing countries using a risk factor-based model and 2015 population estimates. We estimated the in-hospital RSV-ALRI mortality by combining in-hospital case fatality ratios with hospital admission estimates from hospital-based (published and unpublished) studies. We also estimated overall RSV-ALRI mortality by identifying studies reporting monthly data for ALRI mortality in the community and RSV activity. FINDINGS: We estimated that globally in 2015, 33·1 million (uncertainty range [UR] 21·6-50·3) episodes of RSV-ALRI, resulted in about 3·2 million (2·7-3·8) hospital admissions, and 59 600 (48 000-74 500) in-hospital deaths in children younger than 5 years. In children younger than 6 months, 1·4 million (UR 1·2-1·7) hospital admissions, and 27 300 (UR 20 700-36 200) in-hospital deaths were due to RSV-ALRI. We also estimated that the overall RSV-ALRI mortality could be as high as 118 200 (UR 94 600-149 400). Incidence and mortality varied substantially from year to year in any given population. INTERPRETATION: Globally, RSV is a common cause of childhood ALRI and a major cause of hospital admissions in young children, resulting in a substantial burden on health-care services. About 45% of hospital admissions and in-hospital deaths due to RSV-ALRI occur in children younger than 6 months. An effective maternal RSV vaccine or monoclonal antibody could have a substantial effect on disease burden in this age group. FUNDING: The Bill & Melinda Gates Foundation.

Pilot to evaluate the feasibility of measuring seasonal influenza vaccine effectiveness using surveillance platforms in Central-America, 2012.

BACKGROUND: Since 2004, the uptake of seasonal influenza vaccines in Latin America and the Caribbean has markedly increased. However, vaccine effectiveness (VE) is not routinely measured in the region. We assessed the feasibility of using routine surveillance data collected by sentinel hospitals to estimate influenza VE during 2012 against laboratory-confirmed influenza hospitalizations in Costa-Rica, El Salvador, Honduras and Panama. We explored the completeness of variables needed for VE estimation. METHODS: We conducted the pilot case-control study at 23 severe acute respiratory infections (SARI) surveillance hospitals. Participant inclusion criteria included children 6 months-11 years and adults ≥60 years targeted for vaccination and hospitalized for SARI during January-December 2012. We abstracted information needed to estimate target group specific VE (i.e., date of illness onset and specimen collection, preexisting medical conditions, 2012 and 2011 vaccination status and date, and pneumococcal vaccination status for children and adults) from SARI case-reports and for children ≤9 years, inquired about the number of annual vaccine doses given. A case was defined as an influenza virus positive by RT-PCR in a person with SARI, while controls were RT-PCR negative. We recruited 3 controls per case from the same age group and month of onset of symptoms. RESULTS: We identified 1,186 SARI case-patients (342 influenza cases; 849 influenza-negative controls), of which 994 (84 %) had all the information on key variables sought. In 893 (75 %) SARI case-patients, the vaccination status field was missing in the SARI case-report forms and had to be completed using national vaccination registers (36 %), vaccination cards (30 %), or other sources (34 %). After applying exclusion criteria for VE analyses, 541 (46 %) SARI case-patients with variables necessary for the group-specific VE analyses were selected (87 cases, 236 controls among children; 64 cases, 154 controls among older adults) and were insufficient to provide precise regional estimates (39 % for children and 25 % for adults of minimum sample size needed). CONCLUSIONS: Sentinel surveillance networks in middle income countries, such as some Latin American and Caribbean countries, could provide a simple and timely platform to estimate regional influenza VE annually provided SARI forms collect all necessary information.

Demographic and clinical characteristics of deaths associated with influenza A(H1N1) pdm09 in Central America and Dominican Republic 2009-2010.

BACKGROUND: The demographic characteristics of pandemic influenza decedents among middle and low-income tropical countries are poorly understood. We explored the demographics of persons who died with influenza A (H1N1)pdm09 infection during 2009-2010, in seven countries in the American tropics. METHODS: We used hospital-based surveillance to identify laboratory-confirmed influenza deaths in Costa Rica, El Salvador, Guatemala, Honduras, Nicaragua, Panama and Dominican Republic. An influenza death was defined as a person who died within two weeks of a severe acute respiratory infection (SARI) defined as sudden onset of fever >38 °C, cough or sore-throat, and shortness of breath, or difficulty breathing requiring hospitalization, and who tested positive for influenza A (H1N1)pdm09 virus by real time polymerase chain reaction. We abstracted the demographic and clinical characteristics of the deceased from their medical records. RESULTS: During May 2009-June 2010, we identified 183 influenza deaths. Their median age was 32 years (IQR 18-46 years). One-hundred and one (55 %) were female of which 20 (20 %) were pregnant and 7 (7 %) were in postpartum. One-hundred and twelve decedents (61 %) had pre-existing medical conditions, (15 % had obesity, 13 % diabetes, 11 % asthma, 8 % metabolic disorders, 5 % chronic obstructive pulmonary disease, and 10 % neurological disorders). 65 % received oseltamivir but only 5 % received it within 48 h of symptoms onset. CONCLUSIONS: The pandemic killed young adults, pregnant women and those with pre-existing medical conditions. Most sought care too late to fully benefit from oseltamivir. We recommend countries review antiviral treatment policies for people at high risk of developing complications.

Improvements in pandemic preparedness in 8 Central American countries, 2008-2012.

BACKGROUND: In view of ongoing pandemic threats such as the recent human cases of novel avian influenza A(H7N9) in China, it is important that all countries continue their preparedness efforts. Since 2006, Central American countries have received donor funding and technical assistance from the U.S. Centers for Disease Control and Prevention (CDC) to build and improve their capacity for influenza surveillance and pandemic preparedness. Our objective was to measure changes in pandemic preparedness in this region, and explore factors associated with these changes, using evaluations conducted between 2008 and 2012. METHODS: Eight Central American countries scored their pandemic preparedness across 12 capabilities in 2008, 2010 and 2012, using a standardized tool developed by CDC. Scores were calculated by country and capability and compared between evaluation years using the Student's t-test and Wilcoxon Rank Sum test, respectively. Virological data reported to WHO were used to assess changes in testing capacity between evaluation years. Linear regression was used to examine associations between scores, donor funding, technical assistance and WHO reporting. RESULTS: All countries improved their pandemic preparedness between 2008 and 2012 and seven made statistically significant gains (p < 0.05). Increases in median scores were observed for all 12 capabilities over the same period and were statistically significant for eight of these (p < 0.05): country planning, communications, routine influenza surveillance, national respiratory disease surveillance, outbreak response, resources for containment, community interventions and health sector response. We found a positive association between preparedness scores and cumulative funding between 2006 and 2011 (R2 = 0.5, p < 0.01). The number of specimens reported to WHO from participating countries increased significantly from 5,551 (2008) to 18,172 (2012) (p < 0.01). CONCLUSIONS: Central America has made significant improvements in influenza pandemic preparedness between 2008 and 2012. U.S. donor funding and technical assistance provided to the region is likely to have contributed to the improvements we observed, although information on other sources of funding and support was unavailable to study. Gains are also likely the result of countries' response to the 2009 influenza pandemic. Further research is required to determine the degree to which pandemic improvements are sustainable.

Estimated incidence of influenza-virus-associated severe pneumonia in children in El Salvador, 2008-2010.

OBJECTIVE: To estimate the incidence of influenza-virus-associated severe pneumonia among Salvadorian children aged < 5 years. METHODS: Data on children aged < 5 years admitted with severe pneumonia to a sentinel hospital in the western region were collected weekly. Nasal and oropharyngeal swab specimens were collected from a convenience sample of case patients for respiratory virus testing. A health-care utilization survey was conducted in the hospital catchment area to determine the proportion of residents who sought care at the hospital. The incidence of influenza-virus-associated severe pneumonia among all Salvadorian children aged < 5 years was estimated from surveillance and census data, with adjustment for health-care utilization. Influenza virus strains were characterized by the United States Centers for Disease Control and Prevention to determine their correspondence with northern and southern hemisphere influenza vaccine formulations. FINDINGS: Physicians identified 2554 cases of severe pneumonia. Samples from 608 cases were tested for respiratory viruses and 37 (6%) were positive for influenza virus. The estimated incidence of influenza-virus-associated severe pneumonia was 3.2 cases per 1000 person-years (95% confidence interval, CI: 2.8-3.7) overall, 1.5 cases per 1000 person-years (95% CI: 1.0-2.0) during 2008, 7.6 cases per 1000 person-years (95% CI: 6.5-8.9) during 2009 and 0.6 cases per 1000 person-years (95% CI: 0.3-1.0) during 2010. Northern and southern hemisphere vaccine formulations matched influenza virus strains isolated during 2008 and 2010. CONCLUSION: Influenza-virus-associated severe pneumonia occurred frequently among young Salvadorian children during 2008-2010. Antigens in northern and southern hemisphere influenza vaccine formulations corresponded to circulating strains.

Enterovirus D68 infection among hospitalized children with severe acute respiratory illness in El Salvador and Panama, 2012-2013.

We assessed EV-D68 epidemiology and phylogenetics among children aged ≤9 years hospitalized with severe acute respiratory illnesses at five sites in Panama and El Salvador during 2012-2013. Respiratory specimens positive for enterovirus or rhinovirus were tested by real-time RT-PCR for EV-D68, and partial VP1 gene sequences were determined. Of 715 enrolled children, 17 from sites in both countries were EV-D68-positive and commonly had a history of asthma or wheezing. Phylogenetically, 15 of 16 sequences fell into Clade B1, and one into Clade A2. The Central American EV-D68s were closely related genetically to contemporaneous strains from North America, South America, and the Caribbean.

Costs associated with acute respiratory illness and select virus infections in hospitalized children, El Salvador and Panama, 2012-2013.

BACKGROUND AND OBJECTIVES: Although acute respiratory illness (ARI) is a leading cause of hospitalization among young children, few data are available about cost of hospitalization in middle-income countries. We estimated direct and indirect costs associated with severe ARI resulting in hospitalization among children aged <10 years in El Salvador and Panama through the societal perspective. METHODS: During 2012 and 2013, we surveyed caregivers of children hospitalized with ARI about their direct medical (i.e., outpatient consultation, medications, hospital fees), non-medical (transportation, childcare), and indirect costs (lost wages) at discharge and 7 days after discharge. We multiplied subsidized hospital bed costs derived from administrative data by hospitalization days to estimate provider costs. RESULTS: Overall, 638 children were enrolled with a median age of 12 months (IQR 6-23). Their median length of hospitalization was 4 days (IQR 3-6). In El Salvador, caregivers incurred a median of US$38 (IQR 22-72) in direct and indirect costs per illness episode, while the median government-paid hospitalization cost was US$118 (IQR 59-384) generating an overall societal cost of US$219 (IQR 101-416) per severe ARI episode. In Panama, caregivers incurred a median of US$75 (IQR 39-135) in direct and indirect costs, and the health-care system paid US$280 (IQR 150-420) per hospitalization producing an overall societal cost of US$393 (IQR 258-552). CONCLUSIONS: The cost of severe ARI to caregivers and the health care system was substantive. Our estimates will inform models to estimate national costs of severe ARI and cost-benefit of prevention and treatment strategies.

Seasonal influenza vaccine effectiveness against laboratory-confirmed influenza hospitalizations - Latin America, 2013.

BACKGROUND: Despite widespread utilization of influenza vaccines, effectiveness (VE) has not been routinely measured in Latin America. METHODS: We used a case test-negative control design to estimate trivalent inactivated influenza VE against laboratory-confirmed influenza among hospitalized children aged 6months-5years and adults aged ≥60years which are age-groups targeted for vaccination. We sought persons with severe acute respiratory infections (SARI), hospitalized at 71 sentinel hospitals in Argentina, Brazil, Chile, Colombia, Costa Rica, El Salvador, Honduras, Panama, and Paraguay during January-December 2013. Cases had an influenza virus infection confirmed by real-time reverse transcription PCR (rRT-PCR); controls had a negative rRT-PCR result for influenza viruses. We used a two-stage random effects model to estimate pooled VE per target age-group, adjusting for the month of illness onset, age and preexisting medical conditions. RESULTS: We identified 2620 SARI patients across sites: 246 influenza cases and 720 influenza-negative controls aged ≤5years and 448 cases and 1206 controls aged ≥60years. The most commonly identified subtype among participants (48%) was the influenza A(H1N1)pdm09 virus followed by influenza A(H3N2) (34%) and influenza B (18%) viruses. Among children, the adjusted VE of full vaccination (one dose for previously vaccinated or two if vaccine naïve) against any influenza virus SARI was 47% (95% confidence interval [CI]: 14-71%); VE was 58% (95% CI: 16-79%) against influenza A(H1N1)pdm09, and 65% (95% CI: -9; 89%) against influenza A(H3N2) viruses associated SARI. Crude VE of full vaccination against influenza B viruses associated SARI among children was 3% (95% CI: -150; 63). Among adults aged ≥60years, adjusted VE against any influenza SARI was 48% (95% CI: 34-60%); VE was 54% (95% CI: 37-69%) against influenza A(H1N1)pdm09, 43% (95% CI: 18-61%) against influenza A(H3N2) and 34% (95% CI: -4; 58%) against B viruses associated SARI. CONCLUSION: Influenza vaccine provided moderate protection against severe influenza illness among fully vaccinated young children and older adults, supporting current vaccination strategies.

Planning and implementation of an infection control training program for healthcare providers in Latin America.

OBJECTIVE: The lack of well-trained, dedicated infection control personnel prevents optimal control of nosocomial infections in Latin American pediatric oncology centers. We collaboratively planned and implemented a multinational training course in San Salvador, El Salvador, to address this need. METHODS: The course relied on its organizers' experience in training international healthcare providers, the availability of the International Training Center for Nurses, previous infection control collaboration with the Hospital Nacional de Ninos Benjamin Bloom, and resources available at the University of El Salvador. The 4-week course consisted of lecture sessions combined with practical laboratory and hospital experience. RESULTS: Two courses, one conducted in 2005 and one in 2006, trained 44 professionals from 15 Latin American countries. Evaluations showed that course content and teacher performance met the trainees' needs and that all trainees acquired the necessary knowledge and skills. CONCLUSIONS: The course met the need for the training of Latin American infection control practitioners. Our experience can serve as a model for other organizations interested in strengthening infection control and prevention at international sites.

Estimating the burden of influenza-associated hospitalizations and deaths in Central America.

OBJECTIVES: Our objective was to estimate the incidence of influenza-associated hospitalizations and in-hospital deaths in Central American Region. DESIGN AND SETTING: We used hospital discharge records, influenza surveillance virology data, and population projections collected from Costa Rica, El Salvador, Guatemala, Honduras, and Nicaragua to estimate influenza-associated hospitalizations and in-hospital deaths. We performed a meta-analysis of influenza-associated hospitalizations and in-hospital deaths. MAIN OUTCOME MEASURES: The highest annual incidence was observed among children aged <5 years (136 influenza-associated hospitalizations per 100 000 persons). RESULTS: Annually, 7 625-11 289 influenza-associated hospitalizations and 352-594 deaths occurred in the subregion. CONCLUSIONS: Our results suggest that a substantive number of persons are annually hospitalized because of influenza. Health officials should estimate how many illnesses could be averted through increased influenza vaccination.

A randomized, double-blind, placebo-controlled trial evaluating the safety of early oseltamivir treatment among children 0-9 years of age hospitalized with influenza in El Salvador and Panama.

BACKGROUND: Oseltamivir reduces symptom duration among children with uncomplicated influenza, but few data exist on treatment efficacy and tolerability among hospitalized children, particularly among infants aged <1 year. We evaluated tolerability and efficacy of oseltamivir treatment of children aged 0-9 years hospitalized with influenza. METHODS: We conducted a double-blind, randomized, placebo-controlled trial at tertiary care hospitals in El Salvador and Panama. Primary outcomes were length of hospitalization and increased work of breathing. Children were eligible if hospitalized <7 days after symptom onset with cough or sore throat plus tachypnea. Children were randomized 1:1 to receive oseltamivir or placebo; had swabs collected at enrollment for influenza RT-PCR testing; were assessed at enrollment and every 12 h for work of breathing; and were followed for adverse events through 7 days after discharge. Analyses were intention-to-treat. RESULTS: Overall, 683 children were randomized (oseltamivir, n = 341, placebo n = 342). Fifty-three percent were aged <1 year and 30 had influenza (oseltamivir, n = 19; placebo, n = 11). The study was terminated early after enrollment of 21% of the sample size due to lower than anticipated participant accrual. Using Kaplan-Meier analysis, there was no significant difference in median length of hospitalization (3 days, IQR 2-4 vs. 5 days, IQR 3-7, p = 0.22) and increased work of breathing (36 h, IQR 24-72 vs. 96 h, IQR 13-108, p = 0.14) between oseltamivir versus placebo recipients. There was no difference in adverse events between groups. CONCLUSION: Oseltamivir treatment was well tolerated among hospitalized children, including among infants aged <1 year.

Timing of influenza epidemics and vaccines in the American tropics, 2002-2008, 2011-2014.

BACKGROUND: Influenza-associated illness results in increased morbidity and mortality in the Americas. These effects can be mitigated with an appropriately chosen and timed influenza vaccination campaign. To provide guidance in choosing the most suitable vaccine formulation and timing of administration, it is necessary to understand the timing of influenza seasonal epidemics. OBJECTIVES: Our main objective was to determine whether influenza occurs in seasonal patterns in the American tropics and when these patterns occurred. METHODS: Publicly available, monthly seasonal influenza data from the Pan American Health Organization and WHO, from countries in the American tropics, were obtained during 2002-2008 and 2011-2014 (excluding unseasonal pandemic activity during 2009-2010). For each country, we calculated the monthly proportion of samples that tested positive for influenza. We applied the monthly proportion data to a logistic regression model for each country. RESULTS: We analyzed 2002-2008 and 2011-2014 influenza surveillance data from the American tropics and identified 13 (81%) of 16 countries with influenza epidemics that, on average, started during May and lasted 4 months. CONCLUSIONS: The majority of countries in the American tropics have seasonal epidemics that start in May. Officials in these countries should consider the impact of vaccinating persons during April with the Southern Hemisphere formulation.

Associations between seasonal influenza and meteorological parameters in Costa Rica, Honduras and Nicaragua.

Seasonal influenza affects a considerable proportion of the global population each year. We assessed the association between subnational influenza activity and temperature, specific humidity and rainfall in three Central America countries, i.e. Costa Rica, Honduras and Nicaragua. Using virologic data from each country's national influenza centre, rainfall from the Tropical Rainfall Measuring Mission and air temperature and specific humidity data from the Global Land Data Assimilation System, we applied logistic regression methods for each of the five sub-national locations studied. Influenza activity was represented by the weekly proportion of respiratory specimens that tested positive for influenza. The models were adjusted for the potentially confounding co-circulating respiratory viruses, seasonality and previous weeks' influenza activity. We found that influenza activity was proportionally associated (P<0.05) with specific humidity in all locations [odds ratio (OR) 1.21-1.56 per g/kg], while associations with temperature (OR 0.69-0.81 per °C) and rainfall (OR 1.01-1.06 per mm/day) were location-dependent. Among the meteorological parameters, specific humidity had the highest contribution (~3-15%) to the model in all but one location. As model validation, we estimated influenza activity for periods, in which the data was not used in training the models. The correlation coefficients between the estimates and the observed were ≤0.1 in 2 locations and between 0.6-0.86 in three others. In conclusion, our study revealed a proportional association between influenza activity and specific humidity in selected areas from the three Central America countries.

The role of temperature and humidity on seasonal influenza in tropical areas: Guatemala, El Salvador and Panama, 2008-2013.

BACKGROUND: The role of meteorological factors on influenza transmission in the tropics is less defined than in the temperate regions. We assessed the association between influenza activity and temperature, specific humidity and rainfall in 6 study areas that included 11 departments or provinces within 3 tropical Central American countries: Guatemala, El Salvador and Panama. METHOD/FINDINGS: Logistic regression was used to model the weekly proportion of laboratory-confirmed influenza positive samples during 2008 to 2013 (excluding pandemic year 2009). Meteorological data was obtained from the Tropical Rainfall Measuring Mission satellite and the Global Land Data Assimilation System. We found that specific humidity was positively associated with influenza activity in El Salvador (Odds Ratio (OR) and 95% Confidence Interval of 1.18 (1.07-1.31) and 1.32 (1.08-1.63)) and Panama (OR = 1.44 (1.08-1.93) and 1.97 (1.34-2.93)), but negatively associated with influenza activity in Guatemala (OR = 0.72 (0.6-0.86) and 0.79 (0.69-0.91)). Temperature was negatively associated with influenza in El Salvador's west-central departments (OR = 0.80 (0.7-0.91)) whilst rainfall was positively associated with influenza in Guatemala's central departments (OR = 1.05 (1.01-1.09)) and Panama province (OR = 1.10 (1.05-1.14)). In 4 out of the 6 locations, specific humidity had the highest contribution to the model as compared to temperature and rainfall. The model performed best in estimating 2013 influenza activity in Panama and west-central El Salvador departments (correlation coefficients: 0.5-0.9). CONCLUSIONS/SIGNIFICANCE: The findings highlighted the association between influenza activity and specific humidity in these 3 tropical countries. Positive association with humidity was found in El Salvador and Panama. Negative association was found in the more subtropical Guatemala, similar to temperate regions. Of all the study locations, Guatemala had annual mean temperature and specific humidity that were lower than the others.

Establishment of ethical oversight of human research in El Salvador: lessons learned.

Human research is necessary for establishing the best approaches to health care, and should be overseen by a functional research ethics committee. However, in most low-income countries these committees are inadequate in providing the guidelines needed to ensure that ethics remain a prominent feature of human research. We developed a model of interaction with key institutions in low-income countries that had an interest in improving the infrastructure of human participant research. As a result, a research ethics committee was established at three hospitals in El Salvador. The skills gained from developing these committees and the interest shown by the Salvadoran government in rigorous ethical oversight of research involving human participants has allowed the creation of a national ethics committee, which serves as an entity to establish norms and guidelines for further development of research ethics committees in El Salvador. This model of interaction can also be used by institutions in high-income countries to create and strengthen the capacity for ethics in human research in low-income countries.