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Eurosurveillance, Volume 22, Issue 34, 24 August 2017
Research article
Domínguez, Soldevila, Toledo, Godoy, Espejo, Fernandez, Mayoral, Castilla, Egurrola, Tamames, Astray, Morales-Suárez-Varela, and the Working Group of the Project PI12/02079: The effectiveness of influenza vaccination in preventing hospitalisations of elderly individuals in two influenza seasons: a multicentre case–control study, Spain, 2013/14 and 2014/15

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Citation style for this article: Domínguez A, Soldevila N, Toledo D, Godoy P, Espejo E, Fernandez MA, Mayoral JM, Castilla J, Egurrola M, Tamames S, Astray J, Morales-Suárez-Varela M, the Working Group of the Project PI12/02079. The effectiveness of influenza vaccination in preventing hospitalisations of elderly individuals in two influenza seasons: a multicentre case–control study, Spain, 2013/14 and 2014/15. Euro Surveill. 2017;22(34):pii=30602. DOI: http://dx.doi.org/10.2807/1560-7917.ES.2017.22.34.30602

Received:23 August 2016; Accepted:10 January 2017


Introduction

Influenza is an acute illness caused by influenza viruses. During seasonal epidemics, large numbers of influenza infections occur in all age groups. In most individuals, influenza is a self-limiting illness, but serious secondary complications appear in some of those infected with the influenza viruses. Influenza virus infection-related morbidity and mortality is a serious human health concern worldwide, affecting health of populations and economies worldwide. The illness may result in hospitalisation, overwhelming hospitals and causing excess influenza health-related deaths [1]. Worldwide, annual epidemics are estimated to result in ca 3 to 5 million cases of severe illness and ca 250,000 to 500,000 deaths [2]. Individuals who are elderly, especially those with comorbidities, are particularly at risk for influenza-related complications and frequently require hospitalisation. In an American study carried out in the 2005/06 through 2013/14 seasons, 89% of all influenza-associated deaths were in people aged ≥ 65 years [3]. A recent French study estimated that 11% of all-cause deaths in elderly individuals during the influenza season were attributable to influenza [4]. However, mortality is just the tip of the iceberg in terms of disease and the economic burden, and hospitalisation is also an important outcome that should be considered [5].

The capacity of influenza viruses to undergo gradual antigenic change in their surface antigens is a challenge for vaccination against seasonal influenza. Annual administration of the seasonal influenza vaccine, especially in those known to be at high risk of serious complications as a result of influenza, is the focus of current efforts to reduce the disease impact [1]. In the 2013/14 season, the trivalent inactivated vaccine administered in Spain and in all the northern hemisphere, contained an A/California/7/2009(H1N1)pdm-09-like virus, an A(H3N2) virus antigenically similar to the cell-propagated prototype virus A/Victoria/361/2011 and a B/Massachusetts/2/2011-like virus. For the 2014/15 season, the vaccine composition only changed the A/Victoria/361/2011 component to the A/Texas/50/2012 component, an antigenically similar virus.

Various factors affect influenza vaccine effectiveness (VE). One main factor is the antigenic similarity or dissimilarity between circulating strains and vaccine strains: VE decreases with increasing antigenic distance between vaccine components and circulating strains [6]. There was no mismatch in 2013/14 for the A(H1N1)pdm09 and A(H3N2) components but in 2014/15, some degree of mismatch for the A(H3N2) circulating strain was observed [7,8]. Another factor is the influenza illness rate, which may vary substantially from year to year; in years with low rates, the power of some studies to detect significant VE may be compromised [9]. Therefore, studies including more than one season are recommended in order to estimate VE.

The aim of this study was to assess the effectiveness of influenza vaccination in preventing hospitalisation due to laboratory-confirmed influenza in individuals aged ≥ 65 years during two influenza seasons (2013/14 and 2014/15) in Spain.

Methods

Study design

We carried out a multicentre case–control study in 20 major hospitals from seven of 17 Spanish regions (Andalusia, the Basque Country, Catalonia, Castile and Leon, Madrid, Navarra and Valencian Community), covering 1,444,688 individuals aged ≥ 65 years and representing 16.8% of the Spanish population in this age group. Cases and corresponding controls admitted to participating hospitals between December 2013 and March 2015 were recruited.

Selection of cases and controls

We selected patients aged ≥ 65 years who were hospitalised for at least 24 hours with laboratory-confirmed (PCR, culture or immunofluorescence) influenza virus infection.

For each case, up to three matched controls from among patients aged ≥ 65 years with unplanned hospital admission due to causes other than influenza or acute respiratory disease were selected. Controls were matched with each case according to sex, age (± 3 years) and date of hospitalisation (± 10 days). They were selected from patients admitted to the internal medicine, general surgery, otorhinolaryngology, ophthalmology, dermatology or traumatology services wards. Patients referred from nursing homes and those who did not provide written informed consent were excluded.

Data collection

The following demographic variables and pre-existing medical conditions were recorded: age, sex, marital status, educational level, smoking and high alcohol consumption (> 40 g/day for men and > 24 g/day for women), number of hospital visits during the last year, the Barthel Index as a measurement of limitations in activity (ranging from 0 (complete dependence) to 100 (complete independence)), chronic obstructive pulmonary disease (COPD), chronic respiratory failure, history of pneumonia during the last two years, other lung diseases, neoplasia, transplantation, immunosuppressive treatment, asplenia, diabetes mellitus, renal failure, nephrotic syndrome, autoimmune disease, AIDS, asymptomatic HIV infection, congestive heart disease, disabling neurological disease, obesity (body mass index ≥ 30 kg/m2), chronic liver disease, haemoglobinopathy or anaemia, cognitive dysfunction, convulsions and neuromuscular disease. Information on influenza vaccination in the current and previous season, and information on pneumococcal vaccination was collected.

Cases were considered vaccinated with the current influenza vaccine or pneumococcal vaccine if they had received a dose of the vaccine ≥ 14 days before symptom onset. Controls were considered vaccinated if they had received a dose of the influenza vaccine ≥ 14 days before the onset of symptoms of the matched case. Influenza vaccination in the previous season in cases and controls was defined as administration of the seasonal influenza vaccine during the preceding influenza season.

Statistical analysis

A bivariate comparison for matched data of demographic variables and medical conditions between cases and controls was made using McNemar’s test. A two-tailed distribution was assumed for all p values.

A univariate conditional logistic regression model was used to estimate the crude VE in preventing influenza hospitalisation. Propensity score (PS) analysis was used to evaluate the adjusted VE. The PS was created using a logistic regression model with influenza vaccination status as the outcome and demographic variables, medical conditions and functional status as independent variables. The PS was used as a continuous covariate in a final conditional logistic regression model.

Using the formula V E = ( 1     O R )   x   100 , VE was calculated globally, by season, for the presence of high-risk medical conditions, for age groups, for type/subtype of influenza virus and for each category of vaccine exposure: vaccinated only in current season, only in prior season, in both seasons, and unvaccinated in both seasons as the reference group.

The analysis was performed using the SPSS version 23 statistical package and the R version 3.3.0 statistical software [10].

Ethical considerations

All data collected were treated as confidential, in strict observance of legislation on observational studies. The study was approved by the ethics committees of the participating hospitals. Written informed consent was obtained from all patients included in the study.

Results

A total of 728 cases and 1,826 controls were included in the study. The distribution of cases and controls according to demographic variables, medical conditions and vaccination history is shown in Table 1. A total of 359 cases (49.3%) and 1,053 controls (57.7%) had received influenza vaccination. Of the 728 cases, 433 were from the 2013/14 season and 295 were from the 2014/15 season. Of the 433 cases from the 2013/14 season, 429 (99.1%) were infected with influenza A virus (59.8% were A(H1N1)pdm09, 30.5% were A(H3N2) and 8.8% were unsubtyped), two cases were infected with influenza B virus and two cases were missing data for type and subtype. Of the 295 cases from the 2014/15 season, 258 (87.5%) were infected with influenza A virus (22.4% were A(H1N1)pdm09, 42.0% were A(H3N2) and 23.1% were unsubtyped) and 37 (12.5%) were infected with influenza B virus.

Table 1

Distribution of influenza cases and controls aged ≥ 65 years according to demographic variables, medical conditions and history of vaccination, Spain, influenza seasons 2013/14 and 2014/15

Characteristics Cases
(n = 728)
Controls
(n = 1,826)
Crude OR     95% CI     p value
n % n %
Age group
65–79 years 411 56.5 1,016 57.0 Ref Ref 0.50
≥ 80 years 317 43.5 810 43.0 0.89 0.64–1.24
Sex
Female 343 47.1 884 48.4 NA NA NA
Male 385 52.9 942 51.6 NA NA NA
Marital status
Married/cohabiting 450 61.9 1,020 56.0 Ref Ref Ref
Single 39 5.4 145 8.0 0.57 0.39–0.83 0.004
Widowed 217 29.8 615 33.8 0.76 0.61–0.95 0.02
Separated/divorced 21 2.9 42 2.3 1.17 0.68–2.00 0.57
Educational level
Without or primary 560 77.0 1,349 74.9 Ref Ref 0.07
Secondary or higher 167 23.0 453 25.1 0.81 0.64–1.01
Barthel Indexa
0–90a 276 37.9 796 43.6 0.79 0.64–0.96 0.02
> 90a 452 62.1 1,028 56.4 Ref Ref
Smoking status
No smoker 383 52.6 1,057 57.9 Ref Ref 0.01
Smoker/ex-smoker 345 47.4 769 42.1 1.39 1.09–1.77
High alcohol consumptionb
Yes 16 2.2 53 2.9 0.77 0.43–1.38 0.38
No 712 97.8 1,772 97.1 Ref Ref
Number of hospital visits during the past year
0–2 403 56.1 916 50.6 Ref Ref 0.05
≥ 3 316 43.9 896 49.4 0.82 0.67–1.00
High-risk medical conditions
No 104 14.3 386 21.1 Ref Ref < 0.001
Yes 624 85.7 1,440 78.9 1.73 1.35–2.22
Current-season influenza vaccine received
Yes 359 49.3 1,053 57.7 0.73 0.61–0.87 < 0.001
No 369 50.7 773 42.3 Ref Ref
Previous-season influenza vaccine received
Yes 376 51.6 1,054 57.7 0.78 0.66–0.93 0.005
No 352 48.4 772 42.3 Ref Ref
Pneumococcal vaccine received
Yes 372 51.1 836 45.8 1.20 0.99–1.46 0.06
No 356 48.9 990 54.2 Ref Ref

CI: confidence interval; NA: not applicable; OR: odds ratio; Ref: reference group for comparison.

a The Barthel Index is a measurement of limitations in activity, ranging from 0 (complete dependence) to 100 (complete independence).

b High alcohol consumption defined as > 40 g/day for men and > 24 g/day for women.

Most cases (85.7%) and controls (78.9%) had high-risk medical conditions (Table 2).

Table 2

Distribution of influenza cases and controls aged ≥ 65 years according to comorbidities, Spain, influenza seasons 2013/14 and 2014/15

Characteristics Cases
(n = 728)
Controls
(n = 1,826)
Crude OR     95% CI     p value
n % n %
High-risk medical conditions
COPD 194 26.6 218 11.9 3.03 2.37–3.88 < 0.001
Chronic respiratory failure 119 16.3 208 11.4 1.64 1.26–2.14 < 0.001
Pneumonia past 2 years 91 12.5 104 5.7 2.40 1.77–3.26 < 0.001
Other lung disease 238 32.7 380 20.8 1.88 1.54–2.30 < 0.001
Cardiovascular disease 224 30.8 651 35.7 0.84 0.68–1.03 0.09
Diabetes mellitus 235 32.3 666 36.5 0.89 0.74–1.07 0.21
Renal failure with hemodialysis 16 2.2 31 1.7 1.27 0.68–2.37 0.46
Hemaglobinopathy or anaemia 89 12.2 306 16.8 0.68 0.52–0.88 0.004
AIDS 1 0.1 2 0.1 1.30 0.12–14.51 0.83
Asymptomatic HIV infection 3 0.4 1 0.1 9.00 0.94–86.52 0.06
Neurological disease 51 7.0 136 7.4 0.93 0.64–1.33 0.93
Obesity (BMI  ≥ 30 kg/m2) 174 23.9 370 20.3 1.25 1.01–1.56 0.04
Non high-risk medical conditions
Solid organ neoplasia 103 14.1 348 19.1 0.67 0.52–0.85 0.001
Haematologic neoplasia 39 5.4 40 2.2 2.57 1.62–4.07 < 0.001
Transplantation 22 3.0 10 0.5 5.52 2.52–12.09 < 0.001
Immunosuppressive treatment 35 4.8 67 3.7 1.35 0.87–2.08 0.18
Oral corticosteroid therapy 44 6.0 43 2.4 2.54 1.62–3.97 < 0.001
Asplenia 2 0.3 8 0.4 0.66 0.14–3.11 0.60
Renal failure without hemodialysis 135 18.5 341 18.7 1.01 0.80–1.26 0.94
Nephrotic syndrome 7 1.0 14 0.8 1.14 0.45–2.88 0.78
Autoimmune disease 47 6.5 96 5.3 1.38 0.94–2.03 0.10
Chronic liver disease 28 3.8 95 5.2 0.76 0.49–1.18 0.22
Cognitive dysfunction 76 10.4 205 11.2 0.92 0.68–1.23 0.92
Neuromuscular disease 24 3.3 53 2.9 1.16 0.70–1.93 0.55
Convulsions 8 1.1 23 1.3 0.84 0.37–1.92 0.69

BMI: body mass index; CI: confidence interval; COPD: chronic obstructive pulmonary disease; OR: odds ratio.

The overall adjusted VE against influenza hospitalisation in individuals aged ≥ 65 years was 36% (95% CI: 22–47), without relevant differences between seasons (34%, 95% CI: 10–52 in 2013/14 and 37%, 95% CI: 19–51 in 2014/15) (Table 3). The adjusted VE was greater, but not significantly different, in patients without high-risk medical conditions (51%, 95% CI: 15–71) and in patients aged 65–79 years (39%, 95% CI: 20–53). Adjusted VE was 37% (95% CI: 23–48) for all influenza A viruses, 49% (95% CI: 32–62) for influenza A(H1N1)pdm09 and 26% (95% CI: −3 to 47) for influenza A(H3N2). Protection against influenza B was lower (VE 18%, 95% CI: −145 to 73), but the number of cases was very low (statistical power: 10%).

Table 3

Crude and adjusted influenza vaccine effectiveness against hospitalisation because of influenza in individuals aged ≥ 65 years according to influenza season, presence or absence of high-risk medical conditions, case age and type/subtype of influenza virus, Spain, influenza seasons 2013/14 and 2014/15

Variables Cases
vaccinated/n
% Controls
vaccinated/n
% Crude
vaccine
effectiveness
    95% CI     p value Adjusted
vaccine
effectiveness
    95% CI     p value
All 359/728 49.3 1,053/1,826 57.7 27% 13–39 < 0.001 36% 22–47 < 0.001
2013/14 season 208/433 48.0 602/1,038 58.0 31% 13–45 0.002 37% 19–51 < 0.001
2014/15 season 151/295 51.2 451/788 57.2 21% −3 to 40 0.08 34% 10–52 0.01
Non high-risk medical conditions 42/104 40.4 159/255 62.4 54% 27–71 0.001 51% 15–71 0.01
High-risk medical conditions 317/624 50.8 894/1,571 56.9 21% 7–32 0.01 30% 14–44 < 0.001
65–79 years of age 183/411 44.5 561/1,040 53.9 29% 11–44 0.003 39% 20–53 < 0.001
≥ 80 years of age 176/317 55.5 492/786 62.6 24% 0–42 0.05 34% 12–51 0.01
Influenza A 334/687 48.6 991/1,717 57.7 30% 16–41 < 0.001 37% 23–48 < 0.001
Influenza A(H1N1)pdm09 139/325 42.8 464/823 56.4 41% 24–55 < 0.001 49% 32–62 < 0.001
Influenza A(H3N2) 138/256 53.9 393/652 60.3 22% −5 to 42 0.10 26% −3 to 47 0.08a
Influenza B 24/39 61.5 58/103 56.3 −35% −187 to 36 0.43 18% −145 to 73 0.72b

CI: confidence interval

a Statistical power: 74%.

b Statistical power: 10%.

Adjusted VE against hospitalisation was 41% (95% CI: 16–59) among those only vaccinated in the current season and 42% (95% CI: 28–54) among those vaccinated in both the current and previous season. VE among those only vaccinated in the previous season only was 24% (95% CI: −6 to 45) (Table 4).

Table 4

Crude and adjusted influenza vaccine effectiveness against hospitalisation because of influenza in individuals aged ≥ 65 years according to current and previous influenza vaccination, Spain, influenza seasons 2013/14 and 2014/15

Vaccination status Cases
(n = 728)
Controls
(n = 1,826)
Crude
vaccine
effectiveness
    95% CI     p value Adjusted
vaccine
effectiveness
    95% CI     p value
n % n %
Vaccinated in current season only 52 7.1 160 8.8 35% 7–54 0.02 41% 16–59 0.004
Vaccinated in previous season only 69 9.5 161 8.8 13% −20 to 37 0.39 24% −6 to 45 0.11a
Vaccinated in both seasons 307 42.2 893 48.9 28% 13–41 0.001 42% 28–54 < 0.001
Not vaccinated 300 41.2 612 33.5 Ref Ref Ref Ref Ref Ref

CI: confidence interval; Ref: reference group for comparison.

a Statistical power: 54%.

Discussion

The results of this study over two seasons, one with predominant circulation of influenza A (H1N1)pdm09 and one with A(H3N2) predominance, show overall VE against hospitalisation in individuals aged ≥ 65 years was 36% (95% CI: 22–47).

Some studies investigating the prevention of influenza hospitalisation among individuals who are elderly show greater VE [11,12]. In a German study using the screening method, VE in preventing confirmed influenza hospitalisation in individuals aged ≥ 60 years varied between 62% in the 2011/12 season, when the predominant influenza virus strain was A(H3N2), and 83% in the 2010/11 season, when the predominant strain was A(H1N1)pdm09 [11]. However, these levels of VE might be an overestimate because information on comorbidities was not available to adjust them by [13]. A Spanish case–control study for the 2014/15 season, when the predominant strain was A(H3N2), using test-negative controls in 10 hospitals not included in the present study found a VE of 40% (95% CI: 13–59) in terms of preventing hospital admissions in patients 65 years of age and older [14]. A 2014 New Zealand study, also using a test-negative control design, found a VE of 21% (95% CI: −82 to 66) for influenza-related hospitalisation in patients aged ≥ 65 years [15].

An American test-negative study by Petrie et al. [16] during the 2014/15 season found a VE of 48% (95% CI: −33 to 80) in people aged ≥ 65 years, but the number of individuals included was lower than in the present study. A Chinese test-negative study in people aged > 60 years during the two seasons included in our study, but with a lower number of individuals than in our study, found a point estimate of VE of 27% (95% CI: −114 to 75) during the 2013/14 season. However, no effectiveness was observed in the 2014/15 season [17].

The possible influence of increasing age on VE has been investigated. In our study, adjusted VE against hospitalisations was 39% (95% CI: 20–53) in patients aged 65–79 years and 34% (95% CI: 12–51) in patients aged ≥ 80 years. Decreasing effectiveness has been linked to advanced age in different studies [12,18,19]. Senescence diminishes immunity to influenza infections and the response to vaccination, possibly explaining the lower VE in elderly individuals than in the general population [20].

In terms of analysing VE in older age groups, the German study by Remschmidt et al. found that the VE point estimate against laboratory-confirmed influenza was greater in individuals aged 60–69 years than in older individuals in the 2011/12 season, but the opposite was observed in the 2010/11 season [11]. More research is needed to assess this matter.

In our study, VE was 30% (95% CI: 14–44) in patients with high-risk medical conditions, which was lower than that found in patients without these conditions. Similar results were obtained by other studies [16,21]. In contrast, a 2014/15 Canadian test-negative case–control study of individuals aged ≥1 year by Skowronski et al. [22] did not find a lower age-adjusted VE in patients with comorbidities (16%, 95% CI: −28 to 44) than in patients without comorbidities (6%, 95% CI: −20 to 27). Comorbidities, like age, are strongly associated with a lack of response to vaccination [23]. In fact, one of the major mechanisms through which vaccination is thought to reduce mortality is by blunting influenza-triggered exacerbations of underlying diseases [9]. However, despite the limited VE, the benefits of vaccination may be greater in patients with comorbidities because influenza is associated with a higher risk of severe disease and death in these individuals [24].

Similar to the results of other studies of VE in elderly individuals [11,25], the present study found that VE for subtype A(H1N1)pdm09 was greater (49%, 95% CI: 32–62) than that for subtype A(H3N2) (26%, 95% CI: −3 to 47).

Small, non-significant VE differences were found according to season. In the 2013/14 season, an antigenic mismatch was observed in the B virus component but the A(H1N1)pdm09 and A(H3N2) strains circulating were analogous to the seasonal vaccine strains [7]. However, in some Spanish regions, specific mutations of A(H1N1) and A(H3N2) strains associated with low VE and outbreaks in institutions were found [26]. In the 2014/15 season, mismatched A(H3N2) strains circulated widely around the world [27], but only accounted for 60% of influenza A virus isolates in Spain [8]. This might explain why no relevant differences were found in VE in these two influenza seasons.

In our study, VE in individuals vaccinated only in the current season was similar to that of individuals vaccinated in both the current and previous seasons (41%, 95% CI: 16–59 and 42%, 95% CI: 28–54, respectively), which does not support interference between current and previous vaccination. Three 2014/15 influenza season studies carried out on populations of various ages [16,22,28] reported that vaccination in the previous and current season may diminish VE only in the current season, suggesting negative interference from prior vaccination when the antigenic distance between the vaccine and circulating strains is large but the antigenic distance between vaccine components in consecutive seasons is small [22]. The effects of the various combinations of agent-host factors involved in this phenomenon remain unclear and more research is required to determine their influence on vaccine-induced influenza virus immunity in elderly individuals. However, in agreement with Neuzil [29], we consider that the current policy of administering the influenza vaccine every year should be maintained in the meantime. As the most-vulnerable elderly individuals are those with the most advanced age because they have a higher risk of hospitalisation and death compared with healthy elderly individuals aged 65–75 years [20], seasonal influenza vaccination programs in all elderly individuals should be reinforced.

This study has strengths and limitations. Strengths of this study are the matching design, the high number of covariates recorded and the fact that the vaccination status was obtained by consulting hospital records, vaccination cards and primary health registers.

The limitations include the fact that controls were not systematically swabbed and therefore they may, theoretically, have been infected with influenza virus. However, controls were patients with unplanned admission to hospital because of causes other than influenza or acute respiratory disease, and it seems unlikely that selection bias could invalidate our results. A possible confounder is the functional status; however, we included the Barthel Index in the propensity score and therefore this limitation is reasonably controlled for. Likewise, it is important to consider the weeks with influenza activity in the analysis, but because cases and controls were matched by admission date, we believe this is unlikely to invalidate the results. Another possible limitation is that cases and controls were recruited in 20 major hospitals, but as these hospitals cover 16.8% of the Spanish population aged ≥ 65 years we believe that the study is representative of the older Spanish population. Also, we have not collected information on patients’ influenza-like illness in previous seasons, but previous episodes of influenza does not usually act as a confounding factor that needs to be controlled for in studies evaluating influenza VE [30]. Finally, the low statistical power in the investigation of VE against influenza B virus because of the very low number of cases in the two seasons studied was another limitation.

In conclusion, the results of this study show that influenza vaccination was effective in preventing hospitalisations because of influenza in individuals who are elderly. The point estimates of the adjusted VE were highest in patients without high-risk medical conditions, in patients in the 65–79 years of age group and against the influenza A(H1N1)pdm09 subtype compared with the A(H3N2) subtype, although the 95% confidence limits overlapped. Finally, we found that VE was similar between vaccination only in the current season and vaccination in both the current and the previous seasons.


The members of the Project PI12/02079 Working Group are:

Andalusia: J.M. Mayoral (Servicio de Vigilancia de Andalucía), J. Díaz-Borrego (Servicio Andaluz de Salud), A. Morillo (Hospital Universitario Virgen del Rocío), M.J. Pérez-Lozano (Hospital Universitario Virgen de Valme), J. Gutiérrez (Hospital Universitario Puerta del Mar), M. Pérez-Ruiz, M.A. Fernández-Sierra (Complejo Hospitalario Universitario de Granada). Castile and Leon: S. Tamames (Dirección General de Salud Pública, Investigación, Desarrollo e Innovación, Junta de Castilla y León), S. Rojo-Rello (Hospital Clínico Universitario de Valladolid), R. Ortiz de Lejarazu (Universidad de Valladolid), M.I. Fernández-Natal (Complejo Asistencial Universitario de León), T. Fernández-Villa (GIIGAS-Grupo de Investigación en Interacción Gen-Ambiente y Salud, Universidad de León), A. Pueyo (Hospital Universitario de Burgos), Vicente Martin (Universidad de León; CIBERESP). Catalonia: A. Vilella (Hospital Clínic), M. Campins, A. Antón (Hospital Universitari Vall d’Hebron, Universitat Autónoma de Barcelona), G. Navarro (Corporació Sanitària i Universitaria Parc Taulí), M. Riera (Hospital Universitari MútuaTerrassa), E. Espejo (Hospital de Terrassa), M.D. Mas, R. Pérez (ALTHAIA, Xarxa Hospitalaria de Manresa), J.A. Cayla, C. Rius (Agència de Salut Pública de Barcelona; CIBERESP), P. Godoy (Agència de Salut Pública de Catalunya; Institut de Recerca Biomèdica de Lleida, Universitat de Lleida; CIBERESP), N. Torner (Agència de Salut Pública de Catalunya; Universitat de Barcelona; CIBERESP), C. Izquierdo, R. Torra (Agència de Salut Pública de Catalunya), L. Force (Hospital de Mataró), A. Domínguez, N. Soldevila, I. Crespo (Universitat de Barcelona; CIBERESP), D. Toledo (Universitat de Barcelona). Madrid: J. Astray, M.F. Domínguez-Berjon, M.A. Gutiérrez, S. Jiménez, E. Gil, F. Martín, R. Génova-Maleras (Consejería de Sanidad), M.C. Prados, F. Enzzine de Blas, M.A. Salvador, J. Rodríguez, M. Romero (Hospital Universitario la Paz), J.C. Galán, E. Navas, L. Rodríguez (Hospital Ramón y Cajal), C.J. Álvarez, E. Banderas, S. Fernandez (Hospital Universitario 12 de Octubre). Navarra: J. Chamorro (Complejo Hospitalario de Navarra), I. Casado, J. Díaz (Instituto de Salud Pública de Navarra), J. Castilla (Instituto de Salud Pública, Instituto de Investigación Sanitaria de Navarra; CIBERESP). The Basque Country: M. Egurrola, M.J. López de Goicoechea (Hospital de Galdakao). Valencia Community: M. Morales-Suárez-Varela (Universidad de Valencia; CIBERESP), F. Sanz (Consorci Hospital General Universitari de Valencia).

Acknowledgements

Funding: This work was supported by the National Plan of I+D+I 2008–2011 and ISCIII-Subdirección General de Evaluación y Fomento de la Investigación (Project PI12/02079), and co-funded by Fondo Europeo de Desarrollo Regional (FEDER) and the Catalan Agency for the Management of Grants for University Research (AGAUR grant number 2014/ SGR 1403).

The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.

Conflict of interest

None declared.

Authors’ contributions

All the authors participated in the study design, implementation and interpretation. AD, NS and DT had full access to all the study data and take responsibility for the data accuracy of the data analysis. AD and NS designed the study and drafted the report. NS conducted the statistical analysis. PG, EE, MAF, JMM, JC, ME, ST, JA and MMSV designed and supervised the study, and reviewed the draft report. The other members of the Working Group contributed to the design of the study, patient recruitment, data collection and interpretation of the results.


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