Near real-time surveillance of the SARS-CoV-2 epidemic with incomplete data.

Designing public health responses to outbreaks requires close monitoring of population-level health indicators in real-time. Thus, an accurate estimation of the epidemic curve is critical. We propose an approach to reconstruct epidemic curves in near real time. We apply this approach to characterize the early SARS-CoV-2 outbreak in two Spanish regions between March and April 2020. We address two data collection problems that affected the reliability of the available real-time epidemiological data, namely, the frequent missing information documenting when a patient first experienced symptoms, and the frequent retrospective revision of historical information (including right censoring). This is done by using a novel back-calculating procedure based on imputing patients' dates of symptom onset from reported cases, according to a dynamically-estimated "backward" reporting delay conditional distribution, and adjusting for right censoring using an existing package, NobBS , to estimate in real time (nowcast) cases by date of symptom onset. This process allows us to obtain an approximation of the time-varying reproduction number ( R t ) in real-time. At each step, we evaluate how different assumptions affect the recovered epidemiological events and compare the proposed approach to the alternative procedure of merely using curves of case counts, by report day, to characterize the time-evolution of the outbreak. Finally, we assess how these real-time estimates compare with subsequently documented epidemiological information that is considered more reliable and complete that became available later in time. Our approach may help improve accuracy, quantify uncertainty, and evaluate frequently unstated assumptions when recovering the epidemic curves from limited data obtained from public health surveillance systems in other locations.

Lockdown measures and relative changes in the age-specific incidence of SARS-CoV-2 in Spain.

During the first months of the severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) epidemic in 2020, Spain implemented an initial lockdown period on 15 March followed by a strengthened lockdown period on 30 March when only essential workers continued to commute to work. However, little is known about the epidemic dynamics in different age groups during these periods.We used the daily number of coronavirus 2019 cases (by date of symptom onset) reported to the National Epidemiological Surveillance Network among individuals aged 15-19 years through 65-69 years. For each age group g, we computed the proportion PrE(g) of individuals in age group g among all reported cases aged 15-69 years during the pre-lockdown period (1-10 March 2020) and the corresponding proportion PrL(g) during two lockdown periods (initial: 25 March-3 April; strengthened: 8-17 April 2020). For each lockdown period, we computed the proportion ratios PR(g) = PrL(g)/PrE(g). For each pair of age groups g1, g2, PR(g1)>PR(g2) implies a relative increase in the incidence of detected SARS-CoV-2 infection in the age group g1 compared with g2 for the lockdown period vs. the pre-lockdown period.For the initial lockdown period, the highest PR values were in age groups 50-54 years (PR = 1.21; 95% CI: 1.12,1.30) and 55-59 years (PR = 1.19; 1.11,1.27). For the second lockdown period, the highest PR values were in age groups 15-19 years (PR = 1.26; 0.95,1.68) and 50-54 years (PR = 1.20; 1.09,1.31).Our results suggest that different outbreak control measures led to different changes in the relative incidence by age group. During the initial lockdown period, when non-essential work was allowed, individuals aged 40-64 years, particularly those aged 50-59 years, had a higher relative incidence compared with the pre-lockdown period. Younger adults/older adolescents had an increased relative incidence during the later, strengthened lockdown. The role of different age groups during the epidemic should be considered when implementing future mitigation efforts.

Effectiveness of influenza vaccination during pregnancy to prevent severe infection in children under 6 months of age, Spain, 2017-2019.

INTRODUCTION: Influenza vaccination is recommended to pregnant women in Spain to reduce the risk of influenza-related complications. Influenza related hospitalizations pose a significant disease burden in children every year. Although children below 6 months are too young to be vaccinated, they can receive protection against influenza through vaccination of their mothers during pregnancy. We estimated the effectiveness of maternal influenza vaccination to prevent influenza hospitalizations in infants under 6 months of age. METHODS: This is a retrospective pilot study, using data from the Severe Hospitalized Confirmed Influenza Cases (SHCIC) surveillance system in seasons 2017/18 and 2018/19 in Spain. Maternal vaccination status during pregnancy was collected for cases in children 6 months and younger hospitalized with confirmed influenza infection. Influenza vaccine effectiveness was estimated using the screening method, by comparing the proportion of children with vaccinated mothers during pregnancy (proportion of cases vaccinated, PCV), with the vaccination coverage among pregnant women in Spain (proportion of population vaccinated, PPV). RESULTS: For all the study period, the PCV was 17% and the PPV was 35%. Influenza vaccination in mothers during pregnancy prevented influenza confirmed hospitalizations in infants aged 6 months and younger with a 61% (95%CI: 27-79%) effectiveness. CONCLUSIONS: In line with evidence from other countries, influenza vaccination during pregnancy protects infants up to 6 months of age from influenza hospitalizations in Spain. These results support current recommendations of influenza vaccination in pregnant women, and more studies are needed in Spain to confirm the double protection of maternal vaccination in mothers and infants.

European all-cause excess and influenza-attributable mortality in the 2017/18 season: should the burden of influenza B be reconsidered?

OBJECTIVES: Weekly monitoring of European all-cause excess mortality, the EuroMOMO network, observed high excess mortality during the influenza B/Yamagata dominated 2017/18 winter season, especially among elderly. We describe all-cause excess and influenza-attributable mortality during the season 2017/18 in Europe. METHODS: Based on weekly reporting of mortality from 24 European countries or sub-national regions, representing 60% of the European population excluding the Russian and Turkish parts of Europe, we estimated age stratified all-cause excess morality using the EuroMOMO model. In addition, age stratified all-cause influenza-attributable mortality was estimated using the FluMOMO algorithm, incorporating influenza activity based on clinical and virological surveillance data, and adjusting for extreme temperatures. RESULTS: Excess mortality was mainly attributable to influenza activity from December 2017 to April 2018, but also due to exceptionally low temperatures in February-March 2018. The pattern and extent of mortality excess was similar to the previous A(H3N2) dominated seasons, 2014/15 and 2016/17. The 2017/18 overall all-cause influenza-attributable mortality was estimated to be 25.4 (95%CI 25.0-25.8) per 100,000 population; 118.2 (116.4-119.9) for persons aged 65. Extending to the European population this translates into over-all 152,000 deaths. CONCLUSIONS: The high mortality among elderly was unexpected in an influenza B dominated season, which commonly are considered to cause mild illness, mainly among children. Even though A(H3N2) also circulated in the 2017/18 season and may have contributed to the excess mortality among the elderly, the common perception of influenza B only having a modest impact on excess mortality in the older population may need to be reconsidered.

Hepatitis C hospitalizations in Spain, 2004-2013: a retrospective epidemiological study.

BACKGROUND: Hepatitis C is an important public health problem about which there is currently scarce epidemiological information. The objective of this study is to describe and analyse the demographic and epidemiological characteristics of hospitalized cases of hepatitis C in the Spanish population between 2004 and 2013. METHODS: The study uses the Hospital Discharge Records Database of the Spanish National Health System. It is a retrospective descriptive epidemiological study. The variables analysed were year of infection, age, sex, diagnostic category, days admitted and co-morbidity. RESULTS: There have been a total of 351,996 hospitalizations; 225,138 men (64%) and 126,858 women (36%). They are divided between acute hepatitis 8161 (2.3%); chronic hepatitis 325,185 (92.4%) and unspecified hepatitis 18,650 (5.3%). The mean age for men is 53.7 (+/-15.2) and for women 62.3 (+/-17.3). 22.8% also present with an Human immunodeficiency virus (HIV) disease coinfection, and 14.7% with opioid dependencies. The trend is for a gradual increase in cases without statistical significance. CONCLUSIONS: The Hepatitis C cases hospitalized had high levels of chronicity, which entails two distinct patterns of illness in men and women - who are affected in different age ranges.

Pilot study to harmonize the reported influenza intensity levels within the Spanish Influenza Sentinel Surveillance System (SISSS) using the Moving Epidemic Method (MEM).

The intensity of annual Spanish influenza activity is currently estimated from historical data of the Spanish Influenza Sentinel Surveillance System (SISSS) using qualitative indicators from the European Influenza Surveillance Network. However, these indicators are subjective, based on qualitative comparison with historical data of influenza-like illness rates. This pilot study assesses the implementation of Moving Epidemic Method (MEM) intensity levels during the 2014-2015 influenza season within the 17 sentinel networks covered by SISSS, comparing them to historically reported indicators. Intensity levels reported and those obtained with MEM at the epidemic peak of the influenza wave, and at national and regional levels did not show statistical difference (P = 0·74, Wilcoxon signed-rank test), suggesting that the implementation of MEM would have limited disrupting effects on the dynamic of notification within the surveillance system. MEM allows objective influenza surveillance monitoring and standardization of criteria for comparing the intensity of influenza epidemics in regions in Spain. Following this pilot study, MEM has been adopted to harmonize the reporting of intensity levels of influenza activity in Spain, starting in the 2015-2016 season.

Estimating influenza vaccine effectiveness in Spain using sentinel surveillance data.

We aimed to estimate influenza vaccine effectiveness (VE) against laboratory-confirmed influenza during three influenza seasons (2010/11 to 2012/2013) in Spain using surveillance data and to compare the results with data obtained by the cycEVA study, the Spanish component of the Influenza Monitoring Vaccine Effectiveness (I-MOVE) network. We used the test-negative case­control design, with data from the Spanish Influenza Sentinel Surveillance System (SISS) or from the cycEVA study. Cases were laboratory-confirmed influenza patients with the predominant influenza virus of each season, and controls were those testing negative for any influenza virus. We calculated the overall and age-specific adjusted VE. Although the number of patients recorded in the SISS was three times higher than that in the cycEVA study, the quality of information for important variables, i.e. vaccination status and laboratory results, was high in both studies. Overall, the SISS and cycEVA influenza VE estimates were largely similar during the study period. For elderly patients (> 59 years), the SISS estimates were slightly lower than those of cycEVA, and estimates for children (0­14 years) were higher using SISS in two of the three seasons studied. Enhancing the SISS by collecting the date of influenza vaccination and reducing the percentage of patients with incomplete information would optimise the system to provide reliable annual influenza VE estimates to guide influenza vaccination policies.

Excess mortality among the elderly in European countries, December 2014 to February 2015.

Since December 2014 and up to February 2015, the weekly number of excess deaths from all-causes among individuals ≥ 65 years of age in 14 European countries have been significantly higher than in the four previous winter seasons. The rise in unspecified excess mortality coincides with increased proportion of influenza detection in the European influenza surveillance schemes with a main predominance of influenza A (H3N2) viruses seen throughout Europe in the current season, though cold snaps and other respiratory infections may also have had an effect.

Influenza vaccine effectiveness in Spain 2013/14: subtype-specific early estimates using the cycEVA study.

Adjusted early estimates of the 2013/14 influenza vaccine effectiveness (VE) in Spain for all age groups was 35% (95% CI: -9 to 62), 33% (95% CI: -33 to 67) and 28% (95% CI: -33 to 61) against any influenza virus type, A(H1N1)pdm09 and A(H3N2) viruses, respectively. For the population targeted for vaccination, the adjusted VE was 44% (95% CI: -11 to 72), 36% (95% CI: -64 to 75) and 42% (95% CI: -29 to 74), respectively. These preliminary results in Spain suggest a suboptimal protective effect of the vaccine against circulating influenza viruses.

Influenza vaccine effectiveness estimates in Europe in a season with three influenza type/subtypes circulating: the I-MOVE multicentre case-control study, influenza season 2012/13.

In the fifth season of Influenza Monitoring Vaccine Effectiveness in Europe (I-MOVE), we undertook a multicentre case-control study (MCCS) in seven European Union (EU) Member States to measure 2012/13 influenza vaccine effectiveness against medically attended influenza-like illness (ILI) laboratory confirmed as influenza. The season was characterised by substantial co-circulation of influenza B, A(H1N1)pdm09 and A(H3N2) viruses. Practitioners systematically selected ILI patients to swab ≤7 days of symptom onset. We compared influenza-positive by type/subtype to influenza-negative patients among those who met the EU ILI case definition. We conducted a complete case analysis using logistic regression with study as fixed effect and calculated adjusted vaccine effectiveness (AVE), controlling for potential confounders (age, sex, symptom onset week and presence of chronic conditions). We calculated AVE by type/subtype. Study sites sent 7,954 ILI/acute respiratory infection records for analysis. After applying exclusion criteria, we included 4,627 ILI patients in the analysis of VE against influenza B (1,937 cases), 3,516 for A(H1N1)pdm09 (1,068 cases) and 3,340 for influenza A(H3N2) (730 cases). AVE was 49.3% (95% confidence interval (CI): 32.4 to 62.0) against influenza B, 50.4% (95% CI: 28.4 to 65.6) against A(H1N1)pdm09 and 42.2% (95% CI: 14.9 to 60.7) against A(H3N2). Our results suggest an overall low to moderate AVE against influenza B, A(H1N1)pdm09 and A(H3N2), between 42 and 50%. In this season with many co-circulating viruses, the high sample size enabled stratified AVE by type/subtype. The low estimates indicate seasonal influenza vaccines should be improved to achieve acceptable protection levels.

Geographical spread of influenza incidence in Spain during the 2009 A(H1N1) pandemic wave and the two succeeding influenza seasons.

The aim of this study was to monitor the spatio-temporal spread of influenza incidence in Spain during the 2009 pandemic and the following two influenza seasons 2010-2011 and 2011-2012 using a Bayesian Poisson mixed regression model; and implement this model of geographical analysis in the Spanish Influenza Surveillance System to obtain maps of influenza incidence for every week. In the pandemic wave the maps showed influenza activity spreading from west to east. The 2010-2011 influenza epidemic wave plotted a north-west/south-east pattern of spread. During the 2011-2012 season the spread of influenza was geographically heterogeneous. The most important source of variability in the model is the temporal term. The model of spatio-temporal spread of influenza incidence is a supplementary tool of influenza surveillance in Spain.

Low and decreasing vaccine effectiveness against influenza A(H3) in 2011/12 among vaccination target groups in Europe: results from the I-MOVE multicentre case-control study.

Within the Influenza Monitoring Vaccine Effectiveness in Europe (I-MOVE) project we conducted a multicentre case­control study in eight European Union (EU) Member States to estimate the 2011/12 influenza vaccine effectiveness against medically attended influenza-like illness (ILI) laboratory-confirmed as influenza A(H3) among the vaccination target groups. Practitioners systematically selected ILI / acute respiratory infection patients to swab within seven days of symptom onset. We restricted the study population to those meeting the EU ILI case definition and compared influenza A(H3) positive to influenza laboratory-negative patients. We used logistic regression with study site as fixed effect and calculated adjusted influenza vaccine effectiveness (IVE), controlling for potential confounders (age group, sex, month of symptom onset, chronic diseases and related hospitalisations, number of practitioner visits in the previous year). Adjusted IVE was 25% (95% confidence intervals (CI): -6 to 47) among all ages (n=1,014), 63% (95% CI: 26 to 82) in adults aged between 15 and 59 years and 15% (95% CI: -33 to 46) among those aged 60 years and above. Adjusted IVE was 38% (95%CI: -8 to 65) in the early influenza season (up to week 6 of 2012) and -1% (95% CI: -60 to 37) in the late phase. The results suggested a low adjusted IVE in 2011/12. The lower IVE in the late season could be due to virus changes through the season or waning immunity. Virological surveillance should be enhanced to quantify change over time and understand its relation with duration of immunological protection. Seasonal influenza vaccines should be improved to achieve acceptable levels of protection.

Effectiveness of the 2010-11 seasonal trivalent influenza vaccine in Spain: cycEVA study.

BACKGROUND: In Spain, the influenza vaccine effectiveness (VE) was estimated in the last three seasons using an observational study (cycEVA) conducted in the frame of the Spanish Influenza Sentinel Surveillance System. We aimed to measure the effectiveness of the seasonal trivalent vaccine in preventing influenza like illness (ILI) laboratory-confirmed influenza infection at the end of the season 2010-11. METHODS: We conducted a test-negative case-control study between weeks 50/2010 and 12/2011. Cases were ILI laboratory-confirmed influenza infection and controls were those testing negative. Sentinel physicians collected data on demographic and clinical characteristics, vaccination status, and on covariates related to confounding factors associating with influenza VE. We calculated adjusted odds ratios (OR), using logistic regression and computed influenza VE as (1-OR) × 100. RESULTS: The adjusted influenza VE against A(H1N1)pdm09 infection was 46% (95% confidence interval (95%CI): 0; 72). In A(H1N1)pdm09 infected patients who had received both 2010-11 trivalent influenza seasonal and 2009 monovalent pandemic vaccines, influenza VE was 74% (95%CI: 13; 93). The adjusted influenza VE against B infection was 23% (95%CI: -180; 79). CONCLUSION: The trivalent influenza vaccine 2010-11 showed a moderate VE for preventing ILI laboratory confirmed influenza infections. Influenza VE estimates were higher in patients who had received both 2010-11 seasonal trivalent and 2009 monovalent pandemic vaccines.

Early estimates of the effectiveness of the 2011/12 influenza vaccine in the population targeted for vaccination in Spain, 25 December 2011 to 19 February 2012.

We present early estimates of influenza vaccine effectiveness (VE) in the population targeted for vaccination, during 25 December 2011 to 19 February 2012. The adjusted VE was 55% (95% CI: 3 to 79) against any type of influenza virus and 54% (95% CI: 1 to 79) against influenza A(H3N2) virus. This suggests a moderate protective effect of the vaccine in the targeted population in a late influenza epidemic with limited match between vaccine and circulating strains.

Effectiveness of the 2010/11 seasonal trivalent influenza vaccine in Spain: preliminary results of a case-control study.

We present preliminary results of a case-control study to estimate influenza vaccine effectiveness in Spain, from week 50 of 2010 to week 6 of 2011. The adjusted effectiveness of the vaccine in preventing laboratory-confirmed influenza due to any type of influenza virus was 50% (95% CI: -6 to 77%) for the trivalent seasonal vaccine and 72% (95% CI: 7 to 92%) for both trivalent seasonal and monovalent pandemic vaccines, suggesting a protective effect of seasonal vaccination lower than that reported for the previous season.

"I-MOVE" towards monitoring seasonal and pandemic influenza vaccine effectiveness: lessons learnt from a pilot multi-centric case-control study in Europe, 2008-9.

Within I-MOVE (European programme to monitor seasonal and pandemic influenza vaccine effectiveness (IVE)) five countries conducted IVE pilot case-control studies in 2008-9. One hundred and sixty sentinel general practitioners (GP) swabbed all elderly consulting for influenza-like illness (ILI). Influenza confirmed cases were compared to influenza negative controls. We conducted a pooled analysis to obtain a summary IVE in the age group of >or=65 years. We measured IVE in each study and assessed heterogeneity between studies qualitatively and using the I2 index. We used a one-stage pooled model with study as a fixed effect. We adjusted estimates for age-group, sex, chronic diseases, smoking, functional status, previous influenza vaccinations and previous hospitalisations. The pooled analysis included 138 cases and 189 test-negative controls. There was no statistical heterogeneity (I2=0) between studies but ILI case definition, previous hospitalisations and functional status were slightly different. The adjusted IVE was 59.1% (95% CI: 15.3-80.3%). IVE was 65.4% (95% CI: 15.6-85.8%) in the 65-74, 59.6% (95% CI: -72.6 -90.6%) in the age group of >or=75 and 56.4% (95% CI: -0.2-81.3%) for A(H3). Pooled analysis is feasible among European studies. The variables definitions need further standardisation. Larger sample sizes are needed to achieve greater precision for subgroup analysis. For 2009-10, I-MOVE will extend the study to obtain early IVE estimates in groups targeted for pandemic H1N1 influenza vaccination.

Characterisation of swabbing for virological analysis in the Spanish Influenza Sentinel Surveillance System during four influenza seasons in the period 2002-2006.

This study sought to characterise the swabbing pattern in the Spanish Influenza Sentinel Surveillance System (SISSS) and ascertain to what extent the system meets the guidelines currently being drafted by The European Influenza Surveillance Scheme (EISS). Data on seasons 2002/2003 to 2005/2006 were drawn from SISSS. The study analysed collection and dispatch of swab specimens for virological analysis by reference to variables relating to patient sex, age group, vaccination status, specimen collection period, period of influenza activity, time of swabbing and epidemiological season. SISSS adapts to EISS recommendations with respect to the specimen collection period and period of influenza activity, but there is a tendency to collect fewer specimens than recommended as the age of patients increases, and in the case of elderly patients (65 years and older), frequency of collection is clearly insufficient. Furthermore, sentinel physicians collect a higher percentage of specimens in cases where patients have received the influenza vaccine.

Impact of the meningococcal C conjugate vaccine in Spain: an epidemiological and microbiological decision.

The new meningococcal C conjugate vaccine became available in Spain and was included in the infant vaccination schedule in 2000. A catch-up campaign was carried out in children under six years of age. As a consequence, the incidence of meningococcal disease caused by serogroup C has fallen sharply during the last three epidemiological years in Spain. The risk of contracting serogroup C disease in 2002/2003 fell by 58% when compared with the season before the conjugate vaccine was introduced. There was also an important decrease in mortality. Three deaths due to serogroup C occurred in the age groups targeted for vaccination in 2002/2003, compared with 30 deaths in the same age groups in the season before the launch of the vaccine campaign. In the catch-up campaign the vaccine coverage reached values above 92%. For the 2001, 2002 and 2003 routine childhood immunisation programme coverage values ranged from 90% to 95%. During the past three years a total of 111 cases of serogroup C disease have been reported in patients in the vaccine target group. Most of the vaccination failures occurred during the epidemiological year 2002/2003. Eight (53%) vaccine failures occurred in children who had been routinely immunised in infancy, and could be related to a lost of protection with time since vaccination. The isolation of several B:2a:P1.5 strains (ST-11 lineage) is noteworthy. These may have their origin in C:2a:P1.5 strains which, after undergoing genetic recombination at the capsular operon level, express serogroup B. These strains could have relevant epidemic potential.

Impact of the meningococcal C conjugate vaccine in Spain: an epidemiological and microbiological decision.

The new meningococcal C conjugate vaccine became available in Spain and was included in the infant vaccination schedule in 2000. A catch-up campaign was carried out in children under six years of age. As a consequence, the incidence of meningococcal disease caused by serogroup C has fallen sharply during the last three epidemiological years in Spain. The risk of contracting serogroup C disease in 2002/2003 fell by 58% when compared with the season before the conjugate vaccine was introduced. There was also an important decrease in mortality. Three deaths due to serogroup C occurred in the age groups targeted for vaccination in 2002/2003, compared with 30 deaths in the same age groups in the season before the launch of the vaccine campaign. In the catch-up campaign the vaccine coverage reached values above 92%. For the 2001, 2002 and 2003 routine childhood immunisation programme coverage values ranged from 90% to 95%. During the past three years a total of 111 cases of serogroup C disease have been reported in patients in the vaccine target group. Most of the vaccination failures occurred during the epidemiological year 2002/2003. Eight (53%) vaccine failures occurred in children who had been routinely immunised in infancy, and could be related to a lost of protection with time since vaccination. The isolation of several B:2a:P1.5 strains (ST-11 lineage) is noteworthy. These may have their origin in C:2a:P1.5 strains which, after undergoing genetic recombination at the capsular operon level, express serogroup B. These strains could have relevant epidemic potential.

Biotransformation of a somatostatin analogue in precision-cut liver and kidney slices from rat, dog and man.

1. Cleavage of the glucopyranosyl moiety of the somatostatin analogue SDZ CO 611 results in the formation of the major metabolite, SDZ CO 610, in liver and kidney slices of rat, dog and man, as well as in liver S9 and cytosol of rat and man. 2. The rates of SDZ CO 610 formation (nmol/h/mg slice protein) for all three species were determined in liver slices for 24 h and the relative order was: rat (0.12) > dog (0.096) = man (0.095). The rates of SDZ CO 610 formation (nmol/h/mg slice protein) for all three species in kidney were determined, and the relative order was: rat (0.29) > dog (0.16) > man (0.10). 3. SDZ CO 610 was rapidly formed by rat gut contents in the absence of NADPH, possibly by disaccharide-splitting enzymes. 4. Biotransformation of SDZ CO 611 to SDZ CO 610 in human and rat liver S9 and cytosol was similar to that found in liver slices cultures indicating that cleavage of the glucopyranosyl moiety of SDZ CO 611 could occur in the presence and in the absence of cytochrome P450, possibly by glucosidases in liver cytosol. 5. Rat intestinal homogenate also formed SDZ CO 610 but metabolism was dependent upon NADPH, suggestive of a cytochrome P450-dependent reaction.