RESEARCH ARTICLE Risk factors associated with severe outcomes in adult hospitalized patients according to influenza type and subtype Ana Martı́nez1,2, Núria Soldevila2,3, Arantxa Romero-Tamarit ID2, Núria Torner ID1,2,3, Pere Godoy1,2, Cristina Rius2,4, Mireia Jané1,2, Àngela Domı́nguez ID2,3*, and the Surveillance of Hospitalized Cases of Severe Influenza in Catalonia Working Group¶ 1 Agència de Salut Pública de Catalunya, Generalitat de Catalunya, Barcelona, Spain, 2 CIBER Epidemiologı́a y Salud Pública (CIBERESP), Madrid, Spain, 3 Departament de Medicina, Universitat de a1111111111 Barcelona, Barcelona, Spain, 4 Agència de Salut Pública de Barcelona, Barcelona, Spain a1111111111 a1111111111 ¶ Membership of the Surveillance of Hospitalized Cases of Severe Influenza in Catalonia Working Group is a1111111111 provided in the Acknowledgments. a1111111111 * angela.dominguez@ub.edu Abstract OPEN ACCESS Seasonal influenza is a cause of hospitalization, especially in people with underlying dis- Citation: Martı́nez A, Soldevila N, Romero-Tamarit ease or extreme age, and its severity may differ depending on the types and subtypes of cir- A, Torner N, Godoy P, Rius C, et al. (2019) Risk culating viruses. We investigated the factors associated with ICU admission or death in factors associated with severe outcomes in adult hospitalized patients with severe laboratory-confirmed influenza according to the viral type hospitalized patients according to influenza type and subtype. PLoS ONE 14(1): e0210353. https:// and subtype. An observational epidemiological study was carried out in patients aged �18 doi.org/10.1371/journal.pone.0210353 years from 12 Catalan hospitals between 2010 and 2016. For each reported case we col- Editor: Gourapura J. Renukaradhya, The Ohio State lected demographic, virological and clinical characteristics. A mixed-effects logistic regres- University, UNITED STATES sion model was used to estimate crude and adjusted ORs. 1726 hospitalized patients were Received: September 10, 2018 included: 595 (34.5%) were admitted to the ICU and 224 (13.0%) died. Lower ICU admis- sion was associated with age �75 years in all influenza types and subtypes and with age Accepted: December 20, 2018 65–74 years for type A. In contrast, the 65–74 and �75 years age groups were associated Published: January 11, 2019 with an increased risk of death in all types and subtypes, especially for type B (aOR 27.42, Copyright: © 2019 Martı́nez et al. This is an open 95% CI: 4.95–151.93 and 15.96; 95% CI: 3.01–84.68). The comorbidity most closely associ- access article distributed under the terms of the ated with severe outcomes was immune deficiency, which was associated with death for Creative Commons Attribution License, which permits unrestricted use, distribution, and type B (aOR 9.02, 95% CI: 3.05–26.69) and subtype A(H1N1)pdm09 (aOR 3.16, 95% CI: reproduction in any medium, provided the original 1.77–5.66). Older age was a differential factor for ICU admission and death: it was associ- author and source are credited. ated with lower ICU admission but a risk factor for death. The comorbidity with the closest Data Availability Statement: All relevant data are association with death was immune deficiency, mainly in influenza type B patients. within the manuscript and its Supporting Information files. Funding: This study was supported by the Programme of Surveillance, Prevention and Control of Transmissible Diseases (PREVICET), Introduction CIBER de Epidemiologı́a y Salud Pública Influenza A and B, the two influenza viruses that cause epidemics in humans, are responsible (CIBERESP), Instituto de Salud Carlos III, Madrid and the Catalan Agency for the Management of for substantial annual morbidity and mortality worldwide. Each year an estimated 10–20% of Grants for University Research (AGAUR Grant persons have influenza, although there is significant year-to-year variability in rates of illness Number 2017/SGR 1342). The funders had no role [1]. Annual epidemics result in about 3 million to 5 million cases of severe illness and about PLOS ONE | https://doi.org/10.1371/journal.pone.0210353 January 11, 2019 1 / 15 Risk factors for severe influenza in study design, data collection and analysis, 290,000 to 650,000 deaths worldwide [2]. Most infections are self-limited, requiring no health- decision to publish, or preparation of the care visits, but a proportion of cases present severe complications, mainly in people with manuscript. underlying health conditions and in young children and the elderly. Competing interests: The authors have declared On the basis of antigenic differences, influenza A viruses are categorized into subtypes that no competing interests exist. according to haemagglutinin and neuraminidase, the surface antigens, and influenza B viruses are separated into the Victoria and Yamagata lineages. Influenza A(H1N1)pdm09, influenza A (H3N2) and influenza B viruses co-circulate each year [3,4]. Annual excess mortality appears to have increased over recent decades, perhaps because the number of elderly and immunocompromised individuals has also increased [3], and is typi- cally higher in A(H3N2) infections than in A(H1N1)pdm09 infections [5]. Infection due to influenza B viruses is often perceived to be milder than influenza A virus infection [6]. How- ever, similar clinical features between outpatients infected with seasonal influenza A or B viruses and no clinical differences between influenza A(H1N1)pdm09 and A(H3N2) in the post-pandemic period have been reported [7–9]. In hospitalized patients, some independent factors have been associated with mortality and intensive care unit (ICU) admission [10,11], but studies of the factors associated with severity according to the influenza type or subtype are scarce [12]. Given the year-to-year variability in influenza severity, research on factors associated with poor outcomes for the different types and subtypes is needed to prepare ICU capacity and health resources [13,14]. In October 2010, the Public Health Agency of Catalonia initiated surveillance of severe hos- pitalized cases of influenza to complement the information provided by the influenza sentinel system based on primary healthcare physicians [15]. The effectiveness of antiviral treatment and vaccination in avoiding death in patients included in the surveillance system, with all types and subtypes considered jointly, has been reported previously. Receiving antiviral treat- ment in the first 5 days after symptom onset was effective in avoiding ICU admission and death in hospitalized patients with laboratory-confirmed influenza, and seasonal influenza vaccination was effective in preventing a composite outcome of (ICU admission or death) [16,17]. However, the effect of these control measures against poor outcomes have not been investigated in specific influenza types and subtypes. The aim of this study was to investigate factors associated with ICU admission or death in hospitalized patients with severe laboratory-confirmed influenza according to the viral type and subtype. Material and methods Study design An observational epidemiological case-to-case study was carried out in adult patients hospital- ized due to severe acute influenza virus infection. The surveillance system of severe hospitalized influenza in Catalonia, a region in the north- east of Spain with 7.5 million inhabitants, included 12 hospitals covering a total population of 4,644,543 (62% of the Catalan population). A hospitalized case of severe influenza was defined as a severe case of laboratory-confirmed influenza virus infection that required hospitalization (pneumonia, septic shock, multiorgan failure or any other severe condition, including ICU admission) or who developed clinical signs during hospitalization for other reasons. The diagnosis was confirmed by PCR and/or culture of nasopharyngeal swabs. Respiratory tract samples were processed at each hospital laboratory within 24 hours of receipt. A 300 μL aliquot was taken for total nucleic acid extraction and eluted in 25 μL of RNase-free elution buffer using the automatic QIAsymphony system (Qiagen, Hilden, PLOS ONE | https://doi.org/10.1371/journal.pone.0210353 January 11, 2019 2 / 15 Risk factors for severe influenza Germany) according to the manufacturer’s instructions. Subsequently, two specific one-step multiplex real-time PCR techniques using Stratagene Mx3000P QPCR Systems (Agilent Tech- nologies, Santa Clara, CA, USA) were carried out to type A/B influenza viruses (sensitivity was 10 and 103 copies/μL, respectively) and influenza A virus subtypes (sensitivity was 102, 103 and 10 copies/μL for H1, H3 and H5 RNA, respectively) [18]. Data collected Reported cases of severe laboratory-confirmed influenza requiring hospitalization in persons aged �18 years in influenza seasons (2010–11 to 2015–16) were included. For each reported case the following variables were collected: age, sex, chronic obstructive pulmonary disease (COPD), obesity (BMI >40), diabetes, chronic renal disease, immune defi- ciency (HIV infection or other), chronic cardiovascular disease, chronic liver disease, compli- cations (pneumonia, acute respiratory distress syndrome [ARDS] and multiple organ failure), date of symptom onset, hospital stay, seasonal influenza vaccination status, date of antiviral treatment, ICU admission, death, and type of virus (A or B) and subtype (H1N1pdm09 or H3N2). Cases were considered vaccinated if they had received a dose of influenza vaccine �14 days before symptom onset. The information on vaccination status was collected from medical records. The information for each study variable was collected by public health officers from the sur- veillance units of Catalonia through an epidemiological survey. The primary source of infor- mation was the medical record. Statistical analysis The demographic and clinical characteristics (independent variables) of ICU admission and non-ICU admission, and death and survival (dependent variables), were compared using the Chi square test. A p value <0.05 was considered statistically significant. Possible interactions between independent variables were analysed by logistic regression. Independent variables were checked for collinearity using the variance inflation factor [19]. Because the participating hospitals may not have been homogeneous and there were differ- ences in the number of ICU admissions and deaths between hospitals, a mixed-effects logistic regression model with the variable hospital as a random intercept was constructed to estimate the crude and adjusted odds ratios (OR) and the corresponding 95% confidence intervals (CI). Adjusted OR (aOR) were calculated using the mixed-effects logistic regression model with backward selection of variables, with a cut-off point of p<0.2, and the variable season, known to be a potential confounder was also included in the multivariable analysis. The analysis was performed using the SPSS v.24 statistical package and R v3.5.0 statistical software (http://cran.r-project.org). Ethical considerations All data used in the analysis were collected in the routine public health surveillance activities, as part of the legislated mandate of the Health Department of Catalonia, the competent author- ity for the surveillance of communicable diseases, which is officially authorized to receive, treat and temporarily store personal data on cases of infectious disease [20]. Therefore, all study activities formed part of public health surveillance and were thus exempt from institutional board review and did not require informed consent. All data were fully anonymized. PLOS ONE | https://doi.org/10.1371/journal.pone.0210353 January 11, 2019 3 / 15 Risk factors for severe influenza Results A total of 1726 hospitalized patients aged �18 years were included during the study period. Influenza virus type A was detected in 1483 (85.9%) patients and type B in 243 (14.1%). Of cases with type A influenza virus, 696 (46.9%) had the (H1N1)pdm09 subtype, 388 (26.2%) the A(H3N2) subtype and 399 (26.9%) were not subtyped. Demographic and clinical characteristics for all patients, patients admitted to the ICU and deaths are shown in Tables 1–3. There was no collinearity or interaction between variables. Influenza type A A total of 520 (35.1%) patients required ICU admission and 193 (13.0%) died. In the multivari- able analysis, age 65–74 and �75 years was associated with lower ICU admission (aOR 0.63, 95% CI: 0.46–0.87 and 0.25, 95% CI: 0.18–0.35, respectively). Male sex and obesity were associ- ated with ICU admission and seasonal influenza vaccination was associated with lower ICU admission (aOR 0.72, 95% CI: 0.52–0.98) (Fig 1 and S1 Table). The 65–74 and �75 years age groups were associated with an increased risk of death (aOR 1.69, 95% CI: 1.09–2.62 and 1.78, 95% CI: 1.20–2.65, respectively). Immune deficiency, chronic cardiovascular disease and chronic liver disease were also associated with an increased risk of death. Antiviral treatment was associated with a lower risk of death (Fig 2 and S2 Table). Influenza A(H1N1)pdm09 subtype A total of 276 (39.6%) patients required ICU admission and 95 (13.6%) died. In the multivari- able analysis, age �75 years was associated with lower ICU admission (aOR 0.36, 95% CI: 0.22–0.59). The 65–74 years age group was not associated with ICU admission, but the statisti- cal power was low (43%). Immune deficiency was also associated with ICU admission (Fig 1 and S1 Table). The 65–74 and �75 years age groups were associated with an increased risk of death (aOR 2.46, 95% CI: 1.22–4.97 and 2.13, 95% CI: 1.05–4.30, respectively). Immune deficiency, chronic cardiovascular disease and chronic liver disease were also associated with an increased risk of death. Antiviral treatment administered �48 hours before symptom onset was associated with a lower risk of death (Fig 2 and S2 Table). Influenza A(H3N2) subtype A total of 101 (26.0%) patients required ICU admission and 56 (14.4%) died. In the multivari- able analysis, age �75 years was associated with lower ICU admission (aOR 0.26, 95% CI: 0.14–0.48). The 65–74 years age group was not associated with ICU admission, but the statisti- cal power was low (4%). Chronic liver disease was also associated with ICU admission (Fig 1 and S1 Table). The 65–74 and �75 years age groups were associated with an increased risk of death (aOR 3.95, 95% CI: 1.26–12.37 and 4.35, 95% CI: 1.66–11.43, respectively). Antiviral treatment was associated with a lower risk of death (Fig 2 and S2 Table). Influenza type B A total of 75 (30.9%) patients required ICU admission and 31 (12.8%) died. In the multivari- able analysis, age �75 years was associated with lower ICU admission (aOR 0.47, 95% CI: 0.23–0.94). The 65–74 years age group was not associated with ICU admission, but the statisti- cal power was low (12%). COPD was also associated with ICU admission and chronic PLOS ONE | https://doi.org/10.1371/journal.pone.0210353 January 11, 2019 4 / 15 Risk factors for severe influenza Table 1. Characteristics of all patients hospitalized according to influenza type and subtype. All patients A� B p value A(H1N1)pdm09 A(H3N2) p value n = 1726 n = 1483 n = 243 n = 696 n = 388 (85.9%) (14.1%) (40.3%) (22.5%) Age (years) Mean ± SD 64.4±17.2 64.2±17.2 66.0±17.1 0.13 58.8±16.4 71.9±16.1 <0.01 18–64 807 (46.8%) 707 (47.7%) 100 (41.2%) 0.12 421 (60.5%) 107 (27.6%) <0.01 65–74 328 (19.0%) 273 (18.4%) 55 (22.6%) 132 (19.0%) 65 (16.8%) �75 591 (34.2%) 503 (33.9%) 88 (36.2%) 143 (20.5%) 216 (55.7%) Female 743 (43.0%) 652 (44.0%) 91 (37.4%) 0.06 285 (59.1%) 186 (47.9%) 0.03 Male 983 (57.0%) 831 (56.0%) 152 (62.6%) 411 (40.9%) 202 (52.1%) �1 comorbidity 1317 (76.3%) 1134 (76.5%) 183 (75.3%) 0.69 518 (74.4%) 311 (80.2%) 0.03 No comorbidities 409 (23.7%) 349 (23.5%) 60 (24.7%) 178 (25.6%) 77 (19.8%) COPD 442 (25.6%) 379 (25.6%) 63 (25.9%) 0.90 169 (24.3%) 112 (28.9%) 0.10 Obesity 182 (10.5%) 167 (11.3%) 15 (6.2%) 0.02 86 (12.4%) 33 (8.5%) 0.05 Diabetes 431 (25.0%) 369 (24.9%) 62 (25.5%) 0.83 153 (22.0%) 116 (29.9%) <0.01 Chronic renal disease 236 (13.7%) 196 (13.2%) 40 (16.5%) 0.17 81 (11.6%) 60 (15.5%) 0.07 Immune deficiency 335 (19.4%) 287 (19.4%) 48 (19.8%) 0.88 144 (20.7%) 73 (18.8%) 0.46 Chronic cardiovascular disease 508 (29.4%) 437 (29.5%) 71 (29.2%) 0.94 179 (25.7%) 148 (38.1%) <0.01 Chronic liver disease 113 (6.5%) 93 (6.3%) 20 (8.2%) 0.25 41 (5.9%) 25 (6.4%) 0.71 Onset of symptoms to hospitalization 0.33 <0.01 �2 days 703 (41.0%) 611 (41.5%) 92 (38.2%) 254 (36.9%) 189 (48.7%) >2 days 1010 (59.0%) 861 (58.5%) 149 (61.8%) 435 (63.1%) 199 (51.3%) Antiviral treatment (since symptom onset) Mean ± SD 5.1±4.6 5.0±4.6 6.0±5.0 <0.01 5.2±4.8 4.8±4.6 0.22 �48h symptom onset 437 (25.3%) 391 (27.4%) 46 (19.9%) <0.01 169 (24.9%) 107 (28.9%) 0.02 >48h symptom onset 1073 (62.2%) 931 (65.2%) 142 (61.5%) 467 (68.9%) 226 (61.1%) No 150 (8.7%) 107 (7.5%) 43 (18.6%) 42 (6.2%) 37 (10.0%) Seasonal influenza vaccine 449 (26.0%) 374 (25.5%) 75 (31.0%) 0.07 125 (18.3%) 145 (37.5%) <0.01 Pneumonia 1306 (75.9%) 1113 (75.4%) 193 (79.4%) 0.17 548 (79.1%) 292 (75.3%) 0.15 ARDS 659 (39.0%) 580 (39.9%) 79 (33.2%) 0.05 255 (37.6%) 141 (36.7%) 0.77 Multiorgan failure 176 (10.5%) 151 (10.5%) 25 (10.5%) 0.99 76 (11.3%) 34 (8.9%) 0.21 Hospital stay (days) Mean ± SD 14.8±16.0 14.7±15.8 15.1±17.5 0.75 15.5±15.9 15.0±17.6 0.67 0–14 days 1194 (69.3%) 1029 (69.5%) 165 (67.9%) 0.62 469 (67.5%) 276 (71.3%) 0.19 >14 days 530 (30.7%) 452 (30.5%) 78 (32.1%) 226 (32.5%) 111 (28.7%) ICU admission 595 (34.5%) 520 (35.1%) 75 (30.9%) 0.20 276 (39.6%) 101 (26.0%) <0.01 Death 224 (13.0%) 193 (13.0%) 31 (12.8%) 0.91 95 (13.6%) 56 (14.4%) 0.72 Season <0.01 2010–11 169 (9.8%) 165 (11.1%) 4 (1.6%) 153 (22.0%) 1 (0.3%) 2011–12 122 (7.1%) 116 (7.8%) 6 (2.5%) 0 (0%) 96 (24.7%) 2012–13 118 (6.8%) 52 (3.5%) 66 (27.2%) 35 (5.0%) 7 (1.8%) 2013–14 345 (20.0%) 344 (23.2%) 1 (0.4%) 150 (21.6%) 134 (34.5%) 2014–15 425 (24.6%) 364 (24.5%) 61 (25.1%) 90 (12.9%) 142 (36.6%) 2015–16 547 (31.7%) 442 (29.8%) 105 (43.2%) 268 (38.5%) 8 (2.1%) � Includes types A(H1N1)pdm09, A(H3N2) and 399 not subtyped influenza A virus COPD: chronic obstructive pulmonary disease, ARDS: acute respiratory distress syndrome https://doi.org/10.1371/journal.pone.0210353.t001 PLOS ONE | https://doi.org/10.1371/journal.pone.0210353 January 11, 2019 5 / 15 Risk factors for severe influenza Table 2. Factors associated with ICU admission in hospitalized patients according to influenza type and subtype. ICU admitted patients/All patients ICU ADMITTED PATIENTS (n = 595/1726) A� B p value A(H1N1)pdm09 A(H3N2) p value n = 520 n = 75 n = 276 n = 101 (35.1%) (30.9%) (39.6%) (26.0%) Age (years) Mean ± SD 59.0±15.0 58.7±14.8 61.2±16.2 0.18 56.5±14.4 64.0±15.6 <0.01 18–64 369/807 (45.7%) 330 (63.5%) 39 (52.0%) 0.15 193 (69.9%) 44 (43.6%) <0.01 65–74 118/328 (19.0%) 100 (19.2%) 18 (24.0%) 49 (17.8%) 26 (25.7%) �75 108/591 (18.3%) 90 (17.3%) 18 (24.0%) 34 (12.3%) 31 (30.7%) Female 223/743 (30.0%) 196 (37.7%) 27 (36.0%) 0.78 108 (39.1%) 40 (39.6%) 0.93 Male 372/983 (37.8%) 324 (62.3%) 48 (64.0%) 168 (60.9%) 61 (60.4%) �1 comorbidity 457/1317 (34.7%) 401 (77.1%) 56 (74.7%) 0.64 205 (74.3%) 83 (82.2%) 0.11 No comorbidities 138/409 (33.7%) 119 (22.9%) 19 (25.3%) 71 (25.7%) 18 (17.8%) COPD 161/422 (36.4%) 136 (26.2%) 25 (33.3%) 0.19 72 (26.1%) 28 (27.7%) 0.75 Obesity 80/182 (44.0%) 74 (14.2%) 6 (8.0%) 0.14 39 (14.1%) 15 (14.9%) 0.86 Diabetes 145/431 (33.6%) 126 (24.2%) 19 (25.3%) 0.84 53 (19.2%) 34 (33.7%) <0.01 Chronic renal disease 78/236 (33.1%) 68 (13.1%) 10 (13.3%) 0.95 30 (10.9%) 13 (12.9%) 0.59 Immune deficiency 128/335 (38.2%) 109 (21.0%) 19 (25.3%) 0.39 70 (25.4%) 16 (15.8%) 0.05 Chronic cardiovascular disease 156/508 (30.7%) 143 (27.5%) 13 (17.3%) 0.06 66 (23.9%) 38 (37.6%) 0.01 Chronic liver disease 52/113 (46.0%) 44 (8.5%) 8 (10.7%) 0.53 15 (5.4%) 12 (11.9%) 0.03 Onset of symptoms to hospitalization 0.18 0.12 �2 days 224/703 (31.9%) 201 (39.2%) 23 (31.1%) 100 (36.8%) 46 (45.5%) >2 days 363/1010 (35.9%) 312 (60.8%) 51 (68.9%) 172 (63.2%) 55 (54.5%) Antiviral treatment (since symptom onset) Mean ± SD 5.4±4.7 5.3±4.7 6.4±4.1 0.07 5.1±4.2 5.5±5.1 0.46 �48h symptom onset 136/437 (31.1%) 125 (24.9%) 11 (15.3%) 0.01 62 (23.2%) 26 (26.3%) 0.06 >48h symptom onset 401/1073 (37.4%) 350 (69.6%) 51 (70.8%) 192 (71.9%) 62 (62.6%) No 38/150 (25.3%) 28 (5.6%) 10 (13.9%) 13 (4.9%) 11 (11.1%) Seasonal influenza vaccine 107/449 (23.8%) 90 (17.4%) 17 (23.0%) 0.25 35 (12.9%) 32 (31.7%) <0.01 Pneumonia 451/1306 (34.5%) 395 (76.6%) 56 (74.7%) 0.72 221 (80.7%) 73 (72.3%) 0.08 ARDS 342/659 (51.9%) 301 (59.0%) 41 (56.9%) 0.74 167 (61.9%) 52 (52.0%) 0.09 Multiorgan failure 131/176 (74.4%) 113 (22.5%) 18 (25.0%) 0.63 56 (21.1%) 25 (25.3%) 0.40 Hospital stay (days) Mean ± SD 23.1±20.3 23.1±20.3 23.4±21.0 0.89 26.8±26.3 23.7±19.7 0.28 0–14 days 260/1194 (21.8%) 226 (43.6%) 34 (45.3%) 0.78 119 (43.3%) 41 (41.0%) 0.69 >14 days 333/530 (62.8%) 292 (56.4%) 41 (54.7%) 156 (56.7%) 59 (59.0%) Season <0.01 <0.01 2010–11 66/169 (39.1%) 66 (12.7%) 0 (0%) 57 (20.7%) 0 (0%) 2011–12 44/122 (36.1%) 41 (7.9%) 3 (4.0%) 0 (0%) 31 (30.7%) 2012–13 44/118 (37.3%) 20 (3.8%) 24 (32.0%) 15 (5.4%) 4 (4.0%) 2013–14 130/345 (37.7%) 130 (25.0%) 0 (0%) 73 (26.4%) 26 (25.7%) 2014–15 132/425 (31.1%) 111 (21.3%) 21 (28.0%) 41 (14.9%) 37 (36.6%) 2015–16 179/547 (32.7%) 152 (29.2%) 27 (36.0%) 90 (32.6%) 3 (3.0%) � Includes types A(H1N1)pdm09, A(H3N2) and 399 not subtyped influenza A virus COPD: chronic obstructive pulmonary disease, ARDS: acute respiratory distress syndrome https://doi.org/10.1371/journal.pone.0210353.t002 cardiovascular disease was associated with a lower ICU admission (aOR 0.42, 95% CI: 0.20– 0.89) (Fig 1 and S1 Table). PLOS ONE | https://doi.org/10.1371/journal.pone.0210353 January 11, 2019 6 / 15 Risk factors for severe influenza Table 3. Factors associated with death in hospitalized patients according to influenza type and subtype. Died patients/All patients DIED PATIENTS (n = 595/1726) A� B p value A(H1N1)pdm09 A(H3N2) p value n = 193 n = 31 n = 95 n = 56 (13.0%) (12.8%) (13.6%) (14.4%) Age (years) Mean ± SD 69.1±15.9 68.2±16.2 74.3±12.4 0.04 62.8±16.0 78.2±11.5 <0.01 18–64 74/807 (9.2%) 72 (37.3%) 2 (6.5%) <0.01 46 (48.4%) 7 (12.5%) <0.01 65–74 58/328 (17.7%) 44 (22.8%) 14 (45.2%) 27 (28.4%) 10 (17.9%) �75 92/591 (15.6%) 77 (39.9%) 15 (48.4%) 22 (23.2%) 39 (69.6%) Female 87/743 (11.7%) 76 (39.4%) 11 (35.5%) 0.68 34 (35.8%) 28 (50.0%) 0.09 Male 137/983 (13.9%) 117 (60.6%) 20 (64.5%) 61 (64.2%) 28 (50.0%) �1 comorbidity 191/1317 (14.5%) 163 (84.5%) 28 (90.3%) 0.39 81 (85.3%) 48 (85.7%) 0.94 No comorbidities 33/409 (8.1%) 30 (15.5%) 3 (9.7%) 14 (14.7%) 8 (14.3%) COPD 67/422 (15.2%) 56 (29.0%) 11 (35.5%) 0.46 26 (27.4%) 20 (35.7%) 0.28 Obesity 24/182 (13.2%) 21 (10.9%) 3 (9.7%) 0.84 10 (10.5%) 6 (10.7%) 0.97 Diabetes 60/431 (13.9%) 51 (26.4%) 9 (29.0%) 0.76 24 (25.3%) 15 (26.8%) 0.84 Chronic renal disease 49/236 (20.8%) 38 (19.7%) 11 (35.5%) 0.04 15 (15.8%) 13 (23.2%) 0.26 Immune deficiency 77/335 (23.0%) 64 (33.2%) 13 (41.9%) 0.34 38 (40.0%) 14 (25.0%) 0.06 Chronic cardiovascular disease 84/508 (16.5%) 72 (37.3%) 12 (38.7%) 0.88 36 (37.9%) 26 (46.4%) 0.30 Chronic liver disease 25/113 (22.1%) 23 (11.9%) 2 (6.5%) 0.37 12 (12.6%) 5 (8.9%) 0.49 Onset of symptoms to hospitalization 0.09 0.01 �2 days 93/703 (13.2%) 76 (40.0%) 17 (56.7%) 29 (31.5%) 30 (53.6%) >2 days 127/1010 (12.6%) 114 (60.0%) 13 (43.3%) 63 (68.5%) 26 (46.4%) Antiviral treatment (since symptom onset) Mean ± SD 6.2±6.1 6.3±6.2 5.7±5.1 0.69 5.5±4.8 6.9±7.0 0.24 �48h symptom onset 37/437 (8.5%) 31 (16.7%) 6 (20.7%) 0.54 11 (12.1%) 10 (18.5%) 0.01 >48h symptom onset 145/1073 (13.5%) 128 (68.8%) 17 (58.6%) 71 (78.0%) 30 (55.6%) No 33/150 (22.0%) 27 (14.5%) 6 (20.7%) 9 (9.9%) 14 (25.9%) Seasonal influenza vaccine 63/449 (14.0%) 53 (32.3%) 10 (27.6%) 0.59 18 (19.1%) 22 (39.3%) 0.01 Pneumonia 182/1306 (13.9%) 162 (84.4%) 20 (64.5%) 0.01 80 (85.1%) 46 (82.1%) 0.63 ARDS 134/659 (20.3%) 117 (61.6%) 17 (54.8%) 0.48 57 (61.3%) 29 (52.7%) 0.31 Multiorgan failure 95/176 (54.0%) 82 (43.9%) 13 (41.9%) 0.84 44 (47.8%) 18 (33.3%) 0.09 Hospital stay (days) Mean ± SD 14.6±14.9 14.4±14.9 15.6±15.2 0.67 15.6±16.9 13.6±13.0 0.42 0–14 days 144/1194 (12.1%) 124 (64.2%) 20 (64.5%) 0.98 63 (66.3%) 35 (62.5%) 0.63 >14 days 80/530 (15.1%) 69 (35.8%) 11 (35.5%) 32 (33.7%) 21 (37.5%) Season <0.01 <0.01 2010–11 29/169 (17.2%) 27 (14.0%) 2 (6.5%) 26 (27.4%) 0 (0.0%) 2011–12 15/122 (12.3%) 15 (7.8%) 0 (0.0%) 0 (0.0%) 14 (25.0%) 2012–13 16/118 (13.6%) 5 (2.6%) 11 (35.5%) 4 (4.2%) 0 (0.0%) 2013–14 43/345 (12.5%) 43 (22.3%) 0 (0.0%) 17 (17.9%) 18 (32.1%) 2014–15 61/425 (14.4%) 51 (26.4%) 10 (32.3%) 13 (13.7%) 22 (39.3%) 2015–16 60/547 (11.0%) 52 (26.9%) 8 (25.8%) 35 (36.8%) 2 (3.6%) � Includes types A(H1N1)pdm09, A(H3N2) and 399 not subtyped influenza A virus COPD: chronic obstructive pulmonary disease, ARDS: acute respiratory distress syndrome https://doi.org/10.1371/journal.pone.0210353.t003 The 65–74 and �75 years age groups were associated with an increased risk of death (aOR 27.42, 95% CI: 4.95–151.93 and 15.96, 95% CI: 3.01–84.68, respectively). Chronic renal disease PLOS ONE | https://doi.org/10.1371/journal.pone.0210353 January 11, 2019 7 / 15 Risk factors for severe influenza Fig 1. Factors associated with ICU admission in hospitalized patients according to influenza type and subtype. https://doi.org/10.1371/journal.pone.0210353.g001 and immune deficiency were also associated with an increased risk of death (Fig 2 and S2 Table). Discussion In this series of hospitalized cases of severe influenza recorded from 2010 to 2016 in Catalonia, subtype A(H1N1)pdm09 was the most frequent (40.3%) followed (22.5%) by influenza A (H3N2), while influenza type B was less frequent (14.1%). This distribution is similar to that reported in an Italian study from 2010–11 to 2014–15 (79.1%, 9.8% and 6.6%, respectively) and an international cohort from 2009 to 2015 (45.9%, 38.1% and 16.1%, respectively) [11,21], with the non-subtyped influenza A strains in our study (23.1%) representing an intermediate proportion of those recorded in these studies. Patient with A(H1N1)pdm09 required ICU admission more frequently (39.6%), followed by influenza B patients (30.9%) and A(H3N2) patients (26%). The same order of frequency was registered in the international study carried out during six influenza seasons by Dwyer et al. [21] (5.9%, 5.4% and 3.6%), but in studies carried out in England during five seasons [22] and in France during three seasons [9] influenza B required a slightly higher frequency of ICU PLOS ONE | https://doi.org/10.1371/journal.pone.0210353 January 11, 2019 8 / 15 Risk factors for severe influenza Fig 2. Factors associated with death in hospitalized patients according to influenza type and subtype. https://doi.org/10.1371/journal.pone.0210353.g002 admission than subtype A(H3N2) (10.7% vs 10.5% and 14% vs 11%, respectively). The higher proportions of ICU admissions in our study may be due to the fact that only severe hospital- ized cases were included rather than all the hospitalized cases included in the above mentioned studies. Subtype A(H3N2) had the greatest mortality rate (14.4%), but the differences with respect to subtype A(H1N1)pdm09 and type B were not statistically significant, similar to other studies [9,19,23]. Patients aged �75 years were less frequently admitted to the ICU than those aged 18–64 years in all influenza types/subtypes and the 65–74 years age group was also associated with a lower frequency of ICU admission for all type A patients but the statistical power was low for influenza A subtypes and influenza type B. These results contrast with those related to death, which was higher in patients aged 65–74 and �75 years for all influenza types and subtypes. These differences suggest that age is probably taken into account when deciding whether a severe case should be admitted to the ICU. Possible explanations are that the elderly may be admitted to hospital more frequently with clinically less-severe influenza or, due to personal choice might be less frequently transferred to the ICU [13], and that younger adults are less likely to have serious comorbidities and are more likely to be admitted to the ICU if complica- tions appear [19]. PLOS ONE | https://doi.org/10.1371/journal.pone.0210353 January 11, 2019 9 / 15 Risk factors for severe influenza The association of the 65–74 and �75 years age groups with death was closer for type B and subtype A(H3N2), in agreement with the results of other studies that found high excess mor- tality in patients aged >70 years in years with a high rate of A(H3N2) circulation and which recommended paying more attention to this subtype in the elderly [5], and with studies that found that older age was associated with influenza type B [21,23]. Studies focused only on A (H1N1)pdm09 in Spain and in a cohort study including several countries also found a high risk of death in elderly patients [24,25]. An increased risk of death in older age groups has been also reported in a study that did not differentiate by type/subtypes [26]. Men were more frequently admitted to the ICU than women (37.8% vs. 30.0%) but this association was only significant for type A, with the other types/subtypes having insufficient sta- tistical power. These results are in agreement with those of the crude analysis in a 2010–2012 Canadian study with 62.7% of influenza A cases although the association was lost in the adjusted analysis [13]. In our study, as in others [9,25], sex was not associated with death for any influ- enza type or subtype. In contrast, in a study carried out in Taiwan over three seasons, male sex was associated with an increased risk of death in patients with A(H1N1) but not in those with A (H3N2) or B virus infection [27]. As Klein et al. [28] reported, male-female differences in stud- ies of influenza may be confounded by age and health seeking. We can reasonably rule out con- founding by age because we introduced this variable in the adjusted analysis, but unfortunately we have no information about the health-seeking behaviours of patients included. In our study, 161 patients requiring ICU care had COPD, but this was statistically signifi- cant only for type B. We have not found specific type/subtype analyses in other studies. With- out distinguishing by type/subtype, Taylor et al. [13] found that COPD was more frequent in ICU patients than in non-ICU patients (42.7% vs 30.3%) and Garg et al. [29] found an associa- tion between COPD and ICU admission or death. In a study of severe outcomes in hospital- ized patients with pneumonia and influenza between 2000 and 2012, COPD was associated with an increased risk of ICU admission or death in the univariate but not in the multivariate analysis [30]. Other studies found no association with death [23,24,31,32]. Obesity was associated with ICU admission in influenza A patients. Other studies in the post-pandemic period found not association between obesity and ICU admission [13,33]. A possible explanation is that, as in the case of age, obesity is taken into account when deciding whether a severe case should be admitted to the ICU. No association was found with death for any type or subtype, in agreement with the results of studies of influenza B and influenza A [23]. Specific studies of severe influenza A(H1N1)pdm09 or A(H3N2) also found no associa- tion [24,33]. A meta-analysis suggested that data on obesity and the risk of death should be interpreted with caution, because early antiviral treatment might be a key confounding factor [34]. Patients with chronic renal disease may have higher risk of poor outcomes given their altered response. We found that chronic renal disease was associated with death in influenza type B cases but not in cases of A(H1N1)pdm09 or A(H3N2). In a Spanish study of hospital- ized A(H1N1)pdm09 patients, chronic renal disease was also associated with death [24], but another Spanish study [23] found no association in influenza B or influenza A(H1N1)pdm09 patients. In the study by Van Kerkhove et al. [30] in hospitalized patients with influenza and pneumonia between 2000 and 2012, chronic renal disease was associated with severity. We found that immune deficiency was associated with ICU admission and death in influ- enza A(H1N1)pdm09 patients. Lynfield et al. found that immune deficiency was the only comorbidity associated with death in hospitalized A(H1N1)pdm09 patients [25] and Alvarez Lerma et al. [24] found an association between A(H1N1)pdm09 patients who died and immu- nosuppression. In studies that did not separate by type/subtype, an association was found between immunosuppression and ICU admission or death [13,29]. PLOS ONE | https://doi.org/10.1371/journal.pone.0210353 January 11, 2019 10 / 15 Risk factors for severe influenza Chronic cardiovascular diseases were a protective factor against ICU admission in influenza B patients and were a risk factor for death in influenza A(H1N1)pdm09 patients. The surpris- ing finding of the protective role of cardiovascular disease against ICU admission is similar to that found by Taylor et al. [13] in the pandemic period but not in the post-pandemic period. The evident benefits of statins in cardiovascular disease might also extend to patients with influenza [35]. Statins are widely recommended in patients with high levels of LDL-choles- terol, diabetes mellitus and a risk of cardiovascular morbidity [36]. Because these diseases are highly prevalent and the use of statins alone or in combination with other drugs is frequent in Spain [37], a possible explanation for this association might be that, in influenza B patients, a history of treatment with statins was more frequent than in influenza A patients. However, we have no information about previous statins uses and are thus unable to explain these results. Chronic liver disease was associated with ICU admission in influenza A(H3N2) patients and with death in influenza A(H1N1)pdm09 patients, coinciding with the results of another study that did not differentiate between types or subtypes [30]. Antiviral treatment administered �48 hours after symptom onset prevented death in all influenza A patients considered jointly and also in A(H1N1)pdm09 and A(H3N2) patients considered separately. In influenza B patients, the statistical power was insufficient to detect associations. However, as in studies in Italy and France, fewer influenza B patients received early antiviral treatment than those with influenza A subtypes, supporting the idea that treat- ment should be reinforced for type B patients [11,12]. Our results on the association between early antiviral treatment and survival are similar to those found in studies in influenza A (H1N1) patients [24,27] and a study that did not separate by type/subtypes but with a large majority of influenza A cases [26]. This suggests that antiviral treatment is useful in reducing mortality in all types and subtypes and that early treatment should be reinforced. Seasonal influenza vaccination was associated with a reduced risk of ICU admission in influenza A patients considered globally, but the statistical power was low to detect any associ- ation in type B or in A subtypes. In the Canadian study by Taylor et al. [13] in the post-pan- demic period in which most cases were due to influenza A, vaccination was not associated with reduced ICU admission. Like other studies [9,19,38], we found differences in the vaccina- tion coverage according to type/subtypes: the highest coverage (37.5%) was in A(H3N2) patients, followed by influenza B and influenza A(H1N1)pdm09 patients (31.0% and 18.3%), suggesting lower effectiveness against subtype A(H3N2), which may be explained by more fre- quent mutations in this subtype and difficulties in obtaining the corresponding strain for the vaccine [1,39]. Rizzo et al. [11] reported that, of the 72% of influenza B patients with comorbidities that are indications for seasonal vaccination, only 22% were vaccinated, figures close to ours. We agree that interventions against B type using antiviral treatment and vaccination should be improved. This study, like all observational studies, has strengths and limitations. First, comparative studies between factors associated with severe outcomes according to influenza type and sub- type are scarce and, therefore, our results may help identify them. Secondly, unlike studies based on nonspecific outcomes [5,30], all cases included were laboratory-confirmed and, therefore, the distribution of independent variables corresponds to real severe influenza cases. Thirdly, the sample size permitted a multivariable analysis, therefore reducing the possibility of confounding factors invalidating the results. The limitations include, firstly, the voluntary participation of hospitals, which could lead to selection bias. However, because the hospitals participating in the surveillance system cover more than 60% of the Catalan population and a mixed-effect logistic regression model with hospitals as a random intercept was used, we believe our results might be extensible to severe PLOS ONE | https://doi.org/10.1371/journal.pone.0210353 January 11, 2019 11 / 15 Risk factors for severe influenza hospitalized patients in Catalonia. Secondly, not all influenza A case virus were subtyped. However, because the number of influenza A(H1N1)pdm09 and A(H3N2) cases was high, conclusions about the differences in risk factors related to these two subtypes seem robust. Thirdly, we were not able to investigate differences between the Victoria and Yamagata line- ages because this information was not available. Fourthly, all comparisons were between severe hospitalized cases, and the results cannot be extrapolated to non-severe influenza cases. In conclusion, although possible explanations are not always available, our results suggest that predictors of poor outcomes of influenza may vary by type/subtypes. Older age was a dif- ferential factor in patients hospitalized due to severe influenza with respect to ICU admission and death. While age �65 years was a risk factor for death in all influenza types and subtypes, and especially for type B, age >75 years was associated with lower ICU admission for all influ- enza types and subtypes. The comorbidity with the closest association with death was immune deficiency, mainly in type B patients. Further studies on the virology of hospitalized influenza patients are required. Supporting information S1 Table. Factors associated with ICU admission in hospitalized patients according to influenza type and subtype. (DOC) S2 Table. Factors associated with death in hospitalized patients according to influenza type and subtype. (DOC) Acknowledgments The Surveillance of Hospitalized Cases of Severe Influenza in Catalonia Working Group is composed of: Alsedà M, Álvarez J, Arias C, Balañà PJ, Barrabeig I, Camps N, Carol M, Ferràs J, Ferrús G, Follia N, Godoy P, Bach P, Jané M, Martı́nez A, Minguell S, Parrón I, Plasència E, Sala-Farré MR, Torner N, Torra R, Torres J (Public Health Agency of Catalonia); Caylà J, Gor- rindo P, Rius C (Public Health Agency of Barcelona); Marcos MA, Mosquera MDM, Vilella A (H Clı́nic, Barcelona); Antón A, Pumarola T, Campins M (H Universitari Vall d’Hebrón, Bar- celona); Garcı́a D (H Josep Trueta, Girona); Espejo E (H Terrassa); Freixas N, Riera Garcia M (Mútua Terrassa); Maraver E, Mas D, Pérez R, (H Altahia Manresa); Rebull J (H.Verge de la Cinta, Tortosa); Pou J (H Sant Joan de Déu, Esplugues); Garcı́a-Pardo G, Olona M (H Joan XXIII, Tarragona); Barcenilla F, Castellana D (H Arnau de Vilanova, Lleida) Navarro-Rubio G (Consorci Sanitari Parc Taulı́, Sabadell); Force LL (H Mataró). Author Contributions Conceptualization: Ana Martı́nez, Núria Soldevila, Arantxa Romero-Tamarit, Núria Torner, Pere Godoy, Cristina Rius, Mireia Jané, Àngela Domı́nguez. Data curation: Arantxa Romero-Tamarit, Núria Torner. Formal analysis: Núria Soldevila. Funding acquisition: Núria Torner, Pere Godoy, Àngela Domı́nguez. Investigation: Ana Martı́nez, Núria Torner, Pere Godoy, Àngela Domı́nguez. Methodology: Núria Soldevila. PLOS ONE | https://doi.org/10.1371/journal.pone.0210353 January 11, 2019 12 / 15 Risk factors for severe influenza Project administration: Ana Martı́nez, Mireia Jané, Àngela Domı́nguez. Supervision: Ana Martı́nez, Núria Torner, Cristina Rius, Mireia Jané, Àngela Domı́nguez. Validation: Ana Martı́nez, Arantxa Romero-Tamarit, Núria Torner. Visualization: Ana Martı́nez, Núria Soldevila, Núria Torner, Àngela Domı́nguez. Writing – original draft: Ana Martı́nez, Pere Godoy, Cristina Rius, Mireia Jané, Àngela Domı́nguez. Writing – review & editing: Núria Soldevila, Arantxa Romero-Tamarit, Núria Torner. References 1. Treanor JJ. Influenza (including avian influenza and swine influenza). In: Bennett JE, Dolin R, Blaser MJ, editors. Principles and Practice of Infectious Diseases, 8th ed. Philadelphia: Elsevier; 2015. pp. 2000–2024. 2. WHO. Influenza (Seasonal). 31 Jan 2018. Available from: http://www.who.int/news-room/fact-sheets/ detail/influenza-(seasonal) Cited 7 September 2018. 3. Wright PF, Neuman G, Kawaoka Y. Othomyxoviruses. In: Knipe DM, Howley PM, editors. Fields Virol- ogy, 6th ed. Philadelphia: Wolters Kluwer; 2013. pp.1186–1243. 4. Breese JS, Fry AM, Sambhara S, Cox NJ. Inactivated influenza vaccines. In: Plotkin SA, Orenstein WA, Offit PA, Edwards KM, editors. Plotkin’s Vaccines, 7th ed. Philadelphia: Elsevier, 2018. pp. 456– 488. 5. Ribas Freitas A, Donalisio MR. Excess of mortality in adults and elderly and circulation of subtypes of influenza virus in Southern Brazil. Front Immunol. 2018; 8:1903. https://doi.org/10.3389/fimmu.2017. 01903 PMID: 29375560 6. Su S, Chaves SS, Perez A, D’Mello T, Kirley PD, Yousey-Hindes K, et al. Comparing clinical character- istics between hospitalized adults with laboratory-confirmed influenza A and B virus infection. Clin Infect Dis. 2014; 59: 252–255. https://doi.org/10.1093/cid/ciu269 PMID: 24748521 7. Irving SA, Patel DC, Kieke BA, Donahue JG, Vandermause MF, Shay DK, et al. Comparison of clinical features and outcomes of medically attended influenza A and influenza B in a defined population over four season: 2004–2005 through 2007–2008. Influenza Other Respir Viruses. 2012; 6: 37–43. https:// doi.org/10.1111/j.1750-2659.2011.00263.x PMID: 21668663 8. Yang SQ, Qu JX, Wang C, Yu XM, Liu YM, Cao B. Influenza pneumonia among adolescents and adults: a concurrent comparison between influenza A (H1N1) pdm09 and A (H3N2) in the post-pandemic period. Clin Respir J. 2014; 8: 185–191. https://doi.org/10.1111/crj.12056 PMID: 24106842 9. Loubet P, Samih-Lenzi N, Galtier F, Vanhems P, Loulergue P, Duval X, et al. Factors associated with poor outcomes among adults hospitalized for influenza in France: A three-year prospective multicenter study. J Clin Virol. 2016; 79: 68–73. https://doi.org/10.1016/j.jcv.2016.04.005 PMID: 27105315 10. Mata-Marı́n LA, Mata-Marı́n JA, Vásquez-Mota VC, Arroyo-Anduiza CI, Gaytán-Martı́nez JE, Manjar- rez-Téllez B, et al. Risk factors associated with mortality in patients infected with influenza A/H1N1 in Mexico. BMC Res Notes. 2015; 8: 432. https://doi.org/10.1186/s13104-015-1349-8 PMID: 26362856 11. Rizzo C, Bella A. The impact of influenza virus B in Italy: myth or reality? J Prev Med Hyg. 2016; 57: E23–E27. PMID: 27346936 12. Chagvardieff A, Persico N, Marmillot C, Badiaga S, Charrel R, Roch A. Prospective comparative study of characteristics associated with influenza A and B in adults. Med Mal Infect 2018; 48: 180–187. https://doi.org/10.1016/j.medmal.2017.11.007 PMID: 29258804 13. Taylor G, Abdesselam K, Pelude L, Fernandes R, Mitchell R, McGeer A, et al. Epidemiological features of influenza in Canadian adult intensive care unit patients. Epidemiol Infect. 2016; 144: 741–750. https://doi.org/10.1017/S0950268815002113 PMID: 26384310 14. Caini S, Spreeuwenberg P, Kusznierz GF, Rudi JM, Owen R, Pennington K, et al. Distribution of influ- enza virus types by age using case-based global surveillance data from twenty-nine countries, 1999– 2014. BMC Infect Dis 2018; 18: 269. https://doi.org/10.1186/s12879-018-3181-y PMID: 29884140 15. Agència de Salut Pública de Catalunya. Pla d’actuació a Catalunya enfront d’una infecció per virus de la grip en fase post-pandèmica. 15 Jan 2018. Available from: http://canalsalut.gencat.cat/web/.content/ home_canal_salut/professionals/temes_de_salut/grip/documents/grippostpan2010.pdf Cited 23 November 2018 PLOS ONE | https://doi.org/10.1371/journal.pone.0210353 January 11, 2019 13 / 15 Risk factors for severe influenza 16. Domı́nguez A, Romero-Tamarit A, Soldevila N, Godoy P, Jané M, Martı́nez A, et al. Effectiveness of antiviral treatment in preventing death in severe hospitalized influenza cases over six seasons. Epide- miol Infect. 2018; 146: 799–808. https://doi.org/10.1017/S0950268818000663 PMID: 29606178 17. Godoy P, Romero A, Soldevila N, Torner N, Jané M, Martı́nez A, et al. Influenza vaccine effectiveness in preventing influenza severity over six seasons from 2010/2011 to 2015/2016: a case-case analysis. Euro Surveill. 2018; 23: pii = 1700732. 18. Suwannakarn K, Payungporn S, Chieochansin T, Samransamruajkit R, Amonsin A, Songserm T, et al. Typing (A/B) and subtyping (H1/H3/H5) of influenza A viruses by multiplex real-time RT-PCR assays. J Virol Methods. 2008; 152: 25–31. https://doi.org/10.1016/j.jviromet.2008.06.002 PMID: 18598722 19. Katz MH. Multivariable analysis, 3rd ed. Cambridge: Cambridge University Press; 2011. 20. Decret 2013/2015, de 15 de setembre, pel qual es crea la Xarxa de Vigilància Epidemiològica i es regu- len els sistemes de notificació de malalties de declaració obligatòria i els brots epidèmics. DOGC 2015; núm 6958: 1–19. 21. Dwyer DE, Lynfield R, Losso MH, Davey RT, Cozzi-Lepri A, Wentworth D, et al. Comparison of the out- comes of individual with medically attended influenza A and B virus infections enrolled in 2 international cohort studies over a 6-year period: 2009–2015. Open Forum Infect Dis. 2017; 4: ofx212. https://doi. org/10.1093/ofid/ofx212 PMID: 29308401 22. Boddington NL, Verlander NQ, Pebody RG. Developing a system to estimate the severity of influenza infection in England: findings from a hospital-based surveillance system between 2010/2011 and 2014/ 2015. Epidemiol Infect 2017; 145: 1461–1470. https://doi.org/10.1017/S095026881700005X PMID: 28166855 23. Gutiérrez-Pizarraya A, Pérez-Romero P, Alvarez R, Aydillo TA, Osorio-Gómez G, Milara-Ibáñez C, et al. Unexpected severity of cases of influenza B infection in patients that required hospitalization dur- ing the first postpandemic wave. J Infect. 2012; 65: 423–430. https://doi.org/10.1016/j.jinf.2012.07.004 PMID: 22820034 24. Álvarez-Lerma F, Marı́n-Corral J, Vilà C, Loeches IM, Barbadillo S, González de Molina FJ, et al. Char- acteristics of patients with hospital-acquired influenza A(H1N1)pdm09 virus admitted to the intensive care unit. J Hosp Infect. 2017; 95: 200–206. https://doi.org/10.1016/j.jhin.2016.12.017 PMID: 28153560 25. Lynfield R, Davey R, Dwyer DE, Losso MH, Wentworth D, Cozzi-Lepri A, et al. Outcomes of influenza A (H1N1)pdm09 virus infection: results from two international cohort studies. PLoS One. 2014; 9: e101785. https://doi.org/10.1371/journal.pone.0101785 PMID: 25004134 26. Lee N, Choi KW, Chan PK, Hui DS, Lui GC, Wong BC, et al. Outcomes of adults hospitalised with severe influenza. Thorax. 2010; 65: 510–515. https://doi.org/10.1136/thx.2009.130799 PMID: 20522848 27. Huang WT, Chang CH, Hsu YF, Chuang JH. Prognostic factors for mortality in patients hospitalized with influenza complications, in Taiwan. Int Health. 2015; 7: 73–75. https://doi.org/10.1093/inthealth/ ihu083 PMID: 25422279 28. Klein SL, Passaretti C, Anker M, Olukoya P, Pekosz A. The impact of sex, gender and pregnancy on 2009 H1N1 disease. Biol Sex Differ 2010; 1: 5. https://doi.org/10.1186/2042-6410-1-5 PMID: 21208468 29. Garg S, Jain S, Dawood FS, Jhung M, Pérez A, D’Mello T, et al. Pneumonia among adults hospitalized with laboratory-confirmed seasonal influenza virus infection-United States, 2005–2008. BMC Infect Dis. 2015; 15: 369. https://doi.org/10.1186/s12879-015-1004-y PMID: 26307108 30. Van Kerkhove MD, Cooper MJ, Eick-Cost AA, Sanchez JL, Riley S. Risk factors for severe outcomes among members of the United States military hospitalized with pneumonia and influenza, 2000–2012. Vaccine. 2015; 3: 6970–6976. 31. Shah NS, Greenberg JA, McNulty MC, Gregg KS, Riddell J, Mangino JE, et al. Severe influenza in 33 US hospitals, 2013–2014: complications and risk factors for death in 507 patients. Infect Control Hosp Epidemiol. 2015; 36: 1251–1260. https://doi.org/10.1017/ice.2015.170 PMID: 26224364 32. Ramos JM, Garcı́a-Navarro MM, González de la Aleja MP, Sánchez-Martı́nez R, Gimeno-Gascón A, Reus S, et al. Seasonal influenza in octogenarians and nonagenarians admitted to a general hospital: epidemiology, clinical presentation and prognostic factors. Rev Esp Quimioter. 2016; 29: 296–301. PMID: 27714398 33. Braun ES, Crawford FW, Desai MM, Meek J, Kirley PD, Miller L, et al. Obesity not associated with severity among hospitalized adults with seasonal influenza virus infection. Infection 2015; 43: 569–575. https://doi.org/10.1007/s15010-015-0802-x PMID: 26148927 34. Sun Y, Wang Q, Yang G, Lin C, Zhang Y, Yang P. Weight and prognosis for influenza A(H1N1)pdm09 infection during the pandemic period between 2009 and 2011: a systematic review of observational studies with meta-analysis. Infect Dis. 2016; 48: 813–822. PLOS ONE | https://doi.org/10.1371/journal.pone.0210353 January 11, 2019 14 / 15 Risk factors for severe influenza 35. Fedson DS. Clinically-initiated research on treating the host response to pandemic influenza. Hum Vac- cin Immunother. 2018; 14: 790–795. https://doi.org/10.1080/21645515.2017.1378292 PMID: 29058516 36. Mostaza JM, Lahoz C, Garcı́a-Iglesias F, Estirado E, Ruiz-Rivas J, González-Alegre T, et al. Use of statins in primary prevention. Inf Ter Sist Nac Salud. 2011; 35: 46–56. 37. Cordero A, Rodrı́guez L, Batalla A, López L, Torres F, Castellano JM, et al. Optimal pharmacological treatment and adherence to medication in secondary prevention of cardiovascular events in Spain: results from the CAPS study. Cardiovasc Ther 2017; 35: e12240. 38. Ishiguro T, Takayanagi N, Kanauchi T, Uozumi R, Kawate E, Takaku Y, et al. Clinical and radiographic comparisons of influenza virus-associated pneumonia among three viral subtypes. Intern Med. 2016; 55: 731–737. https://doi.org/10.2169/internalmedicine.55.5227 PMID: 27041156 39. Cobbey S, Gouma S, Parkhouese K, Chambers B, Ertl HC, Scmader KE, et al. Poor immunogenicity, not vaccine strain egg adaptation, may explain the low H3N2 influenza vaccine effectiveness in 2012– 2013. Clin Infect Dis 2018; 67: 327–33. https://doi.org/10.1093/cid/ciy097 PMID: 29471464 PLOS ONE | https://doi.org/10.1371/journal.pone.0210353 January 11, 2019 15 / 15