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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Respiratory infections caused by the influenza virus can develop severe pneumonia and acute respiratory failure requiring Intensive Care Unit &#40;ICU&#41; admission&#46; One of the possible complications of influenza pneumonia is the presence of community-acquired respiratory co-infection &#40;CARC&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">1</span></a> Our group reported an incidence of coinfection close to 17&#37;&#44; and it was observed an independent association of CARC and ICU mortality&#46;<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">1</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">In recent years&#44; the incidence of Influenza-Associated Pulmonary Aspergillosis &#40;IAPA&#41; has increased&#44; and currently the reported incidence rates range from 9&#37; to 23&#37;&#46;<a class="elsevierStyleCrossRefs" href="#bib0160"><span class="elsevierStyleSup">2&#8211;5</span></a> The appearance of IAPA worsens the prognosis in mechanically ventilated patients&#44; with a mortality rate reported between 50&#37; and 60&#37;&#46;<a class="elsevierStyleCrossRefs" href="#bib0160"><span class="elsevierStyleSup">2&#44;3&#44;6</span></a> However&#44; the incidence of IAPA in critically ill patients and the risks factors related to the development of this entity vary among currently available reports&#44; possibly due to the populations considered&#44; the different definitions used&#44; and the diverse active microbiological search strategies carried out&#46;</p><p id="par0015" class="elsevierStylePara elsevierViewall">Knowing the incidence of <span class="elsevierStyleItalic">Aspergillus</span> spp&#46; isolation &#40;AI&#41; in critically ill patients would help to better characterize the affected type of population and therefore to identify the need to initiate early empirical antifungal treatment&#46; In this context&#44; the aims of our study were to determine the incidence and impact on ICU mortality of AI during the first 24<span class="elsevierStyleHsp" style=""></span>h of admission in a large population of critically ill patients admitted due to proven severe influenza infection&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Material and methods</span><p id="par0020" class="elsevierStylePara elsevierViewall">This is a secondary analysis of an observational and prospective cohort study&#46; Data were obtained from a voluntary registry created by the Spanish Society of Critical Intensive Medicine and Coronary Units &#40;SEMICYUC&#44; Spanish acronym&#41;&#44; in which 184 Spanish ICUs participated between June 2009 and June 2019&#46; The study was approved by the Ethics Committee of the Joan XXIII University Hospital &#40;IRB &#35; 11809&#41; and by each of the participating centers&#46; Informed consent was not obtained from the patients given the observational nature of the study&#44; and the anonymity of the data was guaranteed&#46;</p><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">Study population</span><p id="par0025" class="elsevierStylePara elsevierViewall">All consecutive patients who required admission to the ICU with a diagnosis of respiratory infection by influenza A H1N1&#44; A seasonal&#44; B or other virus were included during the period described&#46; The presence of the virus was determined by performing a real-time polymerase chain reaction &#40;rt-PCR&#41; at each hospital&#44; according to the recommendations of the Infectious Diseases Society of America &#40;IDSA&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">7</span></a> Only patients with respiratory symptoms were analyzed&#44; either due to pneumonia&#44; exacerbation of asthma or acute exacerbation of chronic obstructive pulmonary disease &#40;COPD&#41;&#46; The clinical diagnosis of pneumonia was determined by the current American Thoracic Society &#40;ATS&#41;&#47;IDSA guidelines&#44; including the presence of 2 or more of the following signs and symptoms&#58; fever &#40;&#62;38<span class="elsevierStyleHsp" style=""></span>&#176;C&#41;&#44; cough&#44; bronchial expectoration&#44; and myalgia&#46; These manifestations had to be associated with at least one organ failure &#40;respiratory failure&#44; hemodynamic instability&#44; renal failure or sensorial disturbance&#41;&#46; Patients under 15 years and those admitted to the ICU for reasons other than respiratory causes were excluded&#46;</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">Study variables</span><p id="par0030" class="elsevierStylePara elsevierViewall">Demographic data&#44; comorbidities&#44; laboratory and clinical results were collected&#46; We recorded the need for mechanical ventilation and the presence of shock at ICU admission Severity of illness was determined using the Acute Physiology and Chronic Health Evaluation II &#40;APACHE II&#41; scale calculated on ICU admission&#46; Renal Replacement Therapy &#40;RRT&#41; was recorded during ICU stay&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0125">Definitions of Pulmonary Aspergillosis &#40;PA&#41; and microbiological search for isolation of <span class="elsevierStyleItalic">Aspergillus</span> spp&#46; in respiratory samples</span><p id="par0035" class="elsevierStylePara elsevierViewall">PA diagnosis was defined according to criteria modified recently proposed by Verweij et al&#46;<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">8</span></a>&#58; Proven PA was defined by lung biopsy showing invasive fungal elements and <span class="elsevierStyleItalic">Aspergillus</span> spp<span class="elsevierStyleItalic">&#46;</span> growth on culture or positive <span class="elsevierStyleItalic">Aspergillus</span> spp<span class="elsevierStyleItalic">&#46;</span> PCR in tissue&#46; Probable PA was defined with pulmonary infiltrate and bronchoalveolar lavage &#40;BAL&#41; culture OR cavitating infiltrate and positive sputum&#47;tracheal aspirate for <span class="elsevierStyleItalic">Aspergillus</span> spp&#46; Possible PA was defined with pulmonary infiltrate and positive tracheal aspirate or mini-BAL culture&#46;</p><p id="par0040" class="elsevierStylePara elsevierViewall">The diagnostic procedures for <span class="elsevierStyleItalic">Aspergillus</span> spp&#46; active search were not standardized and were requested upon the attending physicians&#8217; consideration&#46; No information regarding levels of galactomannan in BAL or serum were recorded in our general registry of patients with severe influenza virus pneumonia&#46; Therefore&#44; we do not have data in this regard&#46;</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0130">Objectives</span><p id="par0045" class="elsevierStylePara elsevierViewall">The primary objective of our study was to determine the incidence of AI in respiratory sample within the first 24<span class="elsevierStyleHsp" style=""></span>h of ICU admission&#46; The secondary objectives were to evaluate the general characteristics of critically ill patients with AI<span class="elsevierStyleItalic">&#44;</span> and to determine the risk factors on ICU mortality in patients with influenza infection&#46;</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0135">Statistical analysis</span><p id="par0050" class="elsevierStylePara elsevierViewall">Qualitative variables were expressed as percentages while quantitative variables&#44; as mean and standard deviation &#40;SD&#41; or median and interquartile range 25&#8211;75&#37;&#46; In order to determine clinical differences among groups&#44; the Chi-square and Fisher tests were used for categorical variables&#44; and the Student&#39;s <span class="elsevierStyleItalic">t</span> or Mann&#8211;Withney <span class="elsevierStyleItalic">U</span> test&#44; for quantitative variables&#46;</p><p id="par0055" class="elsevierStylePara elsevierViewall">A multivariate analysis was performed using binary logistic regression &#40;linear analysis&#41; to determine the risk factors for developing AI and to determine the association of variables with ICU mortality&#46; In addition&#44; an automatic and non-linear analysis &#40;Chi-square automatic interaction detection &#91;CHAID&#93;&#41; was performed to determine which variables are most closely related to AI&#46;</p><p id="par0060" class="elsevierStylePara elsevierViewall">A CHAID tree is a graphic representation of a series of decision rules&#46; Beginning with a root node that includes all cases&#44; the tree branches are divided into different child nodes that contain a subgroup of cases&#46; The criterion for branching &#40;or partitioning&#41; is selected after examining all possible values of all available predictive variables&#46; In terminal nodes&#44; a grouping of cases is obtained&#44; in such a way that cases are as homogeneous as possible regarding the dependent variable value&#46;<a class="elsevierStyleCrossRefs" href="#bib0195"><span class="elsevierStyleSup">9&#44;10</span></a> CHAID decision trees are nonparametric procedures that make no assumption of underlying data&#46; This algorithm determines how continuous and&#47;or categorical independent variables best combine in order to predict a binary outcome based on &#8220;if-then&#8221; logic by portioning each independent variable into mutually exclusive subsets founded on homogeneity of the data&#46; For this study&#44; the response variable is the presence or absence of <span class="elsevierStyleItalic">Aspergillus</span> spp&#46; in respiratory samples&#46;</p><p id="par0065" class="elsevierStylePara elsevierViewall">The statistical analysis and the CHAID tree were performed with the statistical program SPSS 20&#46;0 for Windows &#40;IBM&#41;&#46; A value of <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05 is considered significant&#46;</p></span></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0140">Results</span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0145">General characteristics</span><p id="par0070" class="elsevierStylePara elsevierViewall">A total of 4175 patients were included in the initial registry&#44; from which 216 patients were excluded due to lack of clinical outcome on admission&#44; and also 257 other patients&#44; since they had been included in the database but presented influenza infections other than pneumonia&#44; leaving a total of 3702 patients for the present study &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46; The general characteristics of the population are shown in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><elsevierMultimedia ident="tbl0005"></elsevierMultimedia></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0150">Incidence and risk factors for <span class="elsevierStyleItalic">Aspergillus</span> spp&#46; isolation</span><p id="par0075" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Aspergillus</span> spp&#46; was isolated in only in 1&#46;13&#37; &#40;42&#47;3702&#41; of the included patients&#59; among them&#44; 4&#46;8&#37; &#40;2&#47;42&#41; met criteria of proven PA&#44; and the rest&#44; 95&#46;2&#37; &#40;40&#47;42&#41;&#44; had probable&#47;possible PA&#46; Given the small number of patients with AI and the smaller number of patients with proven PA&#44; and in order to reach stronger comparisons&#44; we considered all cases as AI&#46;</p><p id="par0080" class="elsevierStylePara elsevierViewall">AI patients presented a higher severity of illness according to APACHE II score upon ICU admission&#44; and a greater need for invasive mechanical ventilation &#40;IMV&#41;&#44; and vasoactive drugs &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46; Among AI patients&#44; 19&#46;0 &#40;8&#47;42&#41; had hospital-acquired influenza infection&#44; and a higher incidence regarding non-AI patients &#40;6&#46;5&#37; &#91;239&#47;3660&#93; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#41;&#46; Only hematological malignancies &#40;21&#46;4&#37; &#91;9&#47;42&#93; vs 7&#46;1&#37; &#91;263&#47;3660&#93;&#59; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#41; and other immunosuppression &#40;16&#46;6&#37; &#91;7&#47;42&#93; vs 5&#46;3&#37; &#91;186&#47;3660&#93;&#59; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#41; were more frequent in AI patients &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46; Patients with <span class="elsevierStyleItalic">Aspergillus</span> isolation showed more days of hospitalization previous ICU admission &#40;median 1 day&#44; IQR 1&#8211;2 vs median 2 days&#44; IQR 1&#8211;5&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#44; respectively&#41; &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46;</p><p id="par0085" class="elsevierStylePara elsevierViewall">All variables that showed statistical significance in the univariate analysis &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#44; asthma and COPD were included in the multivariate model due to their clinical importance&#46; Male sex &#40;OR&#58; 2&#46;81&#44; 95&#37; CI&#58; 1&#46;24&#8211;6&#46;33&#41;&#44; presence of asthma &#40;OR&#58; 4&#46;56&#44; 95&#37; CI&#58; 1&#46;87&#8211;11&#46;12&#41;&#44; nosocomial-acquired influenza infection &#40;OR&#58; 2&#46;40&#44; 95&#37; CI&#58; 1&#46;03&#8211;5&#46;61&#41;&#44; hematological malignancies &#40;OR&#58; 4&#46;39&#44; 95&#37; CI&#58; 1&#46;92&#8211;10&#46;04&#41;&#44; HIV &#40;OR&#58; 3&#46;83&#44; 95&#37; CI&#58; 1&#46;08&#8211;13&#46;63&#41;&#44; and other immunosuppression &#40;such as chronic corticosteroid treatment or chemotherapy&#41; &#40;OR&#58; 4&#46;87&#44; 95&#37; CI&#58; 1&#46;99&#8211;11&#46;87&#41; were factors independently associated with AI &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>&#41;&#46;</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0155">Risk factors for AI by non-parametric CHAID analysis</span><p id="par0090" class="elsevierStylePara elsevierViewall">In the CHAID analysis&#44; AI was the dependent variable and age&#44; sex&#44; APACHE II score on hospital admission&#44; presence of shock&#44; asthma&#44; COPD&#44; chronic renal failure&#44; hematologic disease&#44; human immunodeficiency virus &#40;HIV&#41;&#44; other immunosuppression and hospital-acquired influenza infection were included as independent variables&#46; A tree with a maximum depth of 3 branches was generated&#44; with a minimum of 50 cases in the parent node and 9 terminal nodes&#46; The automatic CHAID decision tree showed that hematologic disease with an incidence of 3&#46;3&#37; was the variable most closely associated with AI followed of other immunosuppression as second branch division &#40;<a class="elsevierStyleCrossRef" href="#fig0015">Fig&#46; 3</a>&#41;&#46;</p><elsevierMultimedia ident="fig0015"></elsevierMultimedia></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0160">Risk factors associated with mortality</span><p id="par0095" class="elsevierStylePara elsevierViewall">The crude ICU mortality of our cohort was 21&#46;5&#37; &#40;796&#47;3702&#41;&#46; ICU mortality in the AI group of patients was 59&#46;5&#37; &#40;25&#47;42&#41;&#44; almost three times than that observed in non-AI patients &#40;21&#46;0&#37; &#91;771&#47;3660&#93;&#41; &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#41; &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46; Patients who died were older&#44; had a higher level of severity &#40;determined by APACHE II&#41;&#44; and more often required invasive mechanical ventilation and vasoactive drugs on admission compared to survivors &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><p id="par0100" class="elsevierStylePara elsevierViewall">All significant variables associated with ICU-mortality &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41; were included in the multivariate analysis&#46; Hematological disease &#40;OR&#58; 2&#46;62&#44; 95&#37; CI&#58; 1&#46;95&#8211;3&#46;51&#41;&#44; immunosuppression &#40;OR&#58; 2&#46;05&#44; 95&#37; CI&#58; 1&#46;46&#8211;2&#46;88&#41; and AI &#40;OR&#58; 3&#46;24&#44; 95&#37; CI&#58; 1&#46;60&#8211;6&#46;53&#41; were the variables independently associated with ICU mortality&#46; Notably&#44; COPD showed a protective effect &#40;OR&#58; 0&#46;74&#44; 95&#37; CI&#58; 0&#46;59&#8211;0&#46;93&#41; &#40;<a class="elsevierStyleCrossRef" href="#fig0020">Fig&#46; 4</a>&#41;&#46;</p><elsevierMultimedia ident="fig0020"></elsevierMultimedia><p id="par0105" class="elsevierStylePara elsevierViewall">When adjusted&#44; ICU-survival time was determined by Cox hazard proportional analysis&#44; we observed a significant lower survival in AI patients &#40;HR&#58; 1&#46;53&#44; 95&#37; CI&#58; 1&#46;03&#8211;2&#46;38&#41; &#40;<a class="elsevierStyleCrossRef" href="#fig0025">Fig&#46; 5</a>&#41;&#46;</p><elsevierMultimedia ident="fig0025"></elsevierMultimedia></span></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0165">Discussion</span><p id="par0110" class="elsevierStylePara elsevierViewall">The main finding of our study is that the incidence of AI in respiratory sample of critically ill patients with severe influenza pneumonia is low in Spain&#44; and it was closely associated with crude ICU mortality&#46; Another interesting finding is that COPD did not appear as a AI associated factor&#44; while hematological disease or other causes of immunosuppression were highly related with AI development&#46;</p><p id="par0115" class="elsevierStylePara elsevierViewall">To our knowledge&#44; this is the first study to asses the incidence and impact of AI in patients with severe influenza pneumonia within the first 24<span class="elsevierStyleHsp" style=""></span>h of ICU admission&#46; Other studies have evaluated the <span class="elsevierStyleItalic">Aspergillus</span> incidence in an ICU evolution period&#46; This difference makes it difficult to compare between studies&#46; However&#44; given the impact of our results&#44; we believe it is important to highlight some considerations of clinical relevancy&#46;</p><p id="par0120" class="elsevierStylePara elsevierViewall">In our study&#44; AI incidence is notably lower regarding the incidence of IAPA reported by other authors in other countries&#46;<a class="elsevierStyleCrossRefs" href="#bib0165"><span class="elsevierStyleSup">3&#8211;5</span></a> The association between pulmonary aspergillosis &#40;PA&#41; and influenza infection or other respiratory viruses has been described previously&#46;<a class="elsevierStyleCrossRefs" href="#bib0205"><span class="elsevierStyleSup">11&#8211;14</span></a> This association can respond to various factors&#46; Viral infections directly injure the epithelium of the bronchial mucosa&#44;<a class="elsevierStyleCrossRefs" href="#bib0205"><span class="elsevierStyleSup">11&#44;12</span></a> facilitating the invasion by fungi present in the respiratory tract&#46; Furthermore&#44; influenza infection alters cytokines levels at both pulmonary and systemic levels&#44; and the function of pulmonary macrophages and T-lymphocytes&#44; producing a certain degree of immunodeficiency that favors <span class="elsevierStyleItalic">Aspergillus</span> spp&#46; infection&#46;<a class="elsevierStyleCrossRefs" href="#bib0215"><span class="elsevierStyleSup">13&#44;14</span></a></p><p id="par0125" class="elsevierStylePara elsevierViewall">The association between PA and viral infection is frequent in immunosuppressed patients&#46; In a cohort of 219 patients receiving an allogeneic transplant&#44;<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">15</span></a> viral respiratory tract infection was shown to be a risk factor for the development of PA &#40;HR&#58; 4&#46;3&#44; 95&#37; CI&#58; 2&#8211;9&#46;4&#41;&#46; Garc&#237;a-Vidal et al&#46;<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">4</span></a> reported an 8&#46;8&#37; incidence of IAPA in 57 immunosuppressed patients admitted to hospital due to influenza A&#40;H1N1&#41;pdm09 virus infection during the 2009 pandemic&#46; The same author<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">16</span></a> reported an association between influenza virus infection &#40;HR&#58; 2&#46;5&#44; 95&#37; CI&#58; 1&#46;1&#8211;5&#46;8&#41; and parainfluenza &#40;HR&#58; 2&#46;6&#44; 95&#37; CI&#58; 1&#46;6&#8211;4&#46;3&#41; with invasive infection by filamentous fungi&#46; However&#44; in critically ill patients IAPA incidence and risk factors are uncertain and highly variable&#46;<a class="elsevierStyleCrossRefs" href="#bib0235"><span class="elsevierStyleSup">17&#8211;19</span></a> The low incidence of AI in our population &#40;1&#46;1&#37;&#41; differs from that published in other series&#46; Wauters et al&#46;<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">5</span></a> observed a 23&#37; incidence of PA in a cohort of 40 patients with influenza A&#40;H1N1&#41;pdm09 infection&#46; The Dutch&#47;Belgian mycosis study group has recently published<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">3</span></a> an incidence of 19&#37; of IAPA in patients with influenza A&#40;H1N1&#41; virus infection&#44; clearly higher than the 5&#37; observed in the control group of patients admitted for bacterial community-acquired pneumonia&#46; Finally&#44; this group also found a higher incidence of PA within the influenza cohort group of immunocompromised patients versus non-immunocompromised patients &#40;32&#37; vs 14&#37;&#41;&#46; These differences with respect to our results may be related to the characteristics of the studied populations&#44; especially regarding the frequency of immunosuppressed patients&#44; as well as the implemented diagnostic methods and the observation period&#46; The determination of galactomannan in BAL&#44; used in some studies<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">20</span></a> for aspergillosis diagnosis&#44; is a rarely used technique &#40;&#60;20&#37;&#41; in invasive mechanically ventilated patients with community-acquired pneumonia <a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">21</span></a>&#46; The importance of immunosuppression in patients with hematological disease as a risk to AI has been confirmed by our automatic CHAID analysis&#59; this relation was described by Vanderbeke et al&#46;<a class="elsevierStyleCrossRef" href="#bib0260"><span class="elsevierStyleSup">22</span></a> in a recent review&#46; In this regard&#44; the GLIMP study&#44;<a class="elsevierStyleCrossRef" href="#bib0265"><span class="elsevierStyleSup">23</span></a> a multicentric&#44; international&#44; observational point-prevalence study for patients hospitalized due to community-acquired pneumonia&#44; reported that <span class="elsevierStyleItalic">Aspergillus</span><span class="elsevierStyleItalic">fumigatus</span> as the causative pathogen was found more frequently in immunocompromised patients &#40;8 &#91;1&#46;3&#37;&#93; vs 10 &#91;0&#46;4&#37;&#93;&#59; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;01&#41; and that AIDS &#40;OR&#58; 15&#46;10&#44; 95&#37; CI&#58; 6&#46;36&#8211;35&#46;88&#41; and hematological cancer &#40;OR&#58; 4&#46;65&#44; 95&#37; CI&#58; 1&#46;85&#8211;11&#46;69&#41; were independent risk factors for <span class="elsevierStyleItalic">A&#46;</span><span class="elsevierStyleItalic">fumigatus</span>&#46;</p><p id="par0130" class="elsevierStylePara elsevierViewall">Male sex&#44; asthma&#44; nosocomial-acquired influenza infection&#44; and immunosuppression were the variables associated with the risk of presenting AI in our cohort of critically ill patients&#46; The relationship between pulmonary disease &#40;e&#46;g&#46;&#44; asthma and COPD&#41; and PA has been previously studied&#46; It has been proposed that either the chronic inflammatory disease itself or its management&#44; including chronic corticosteroids treatment and broad-spectrum antibiotic therapy&#44; could be the factors which explain this association&#46;<a class="elsevierStyleCrossRefs" href="#bib0270"><span class="elsevierStyleSup">24&#44;25</span></a> Notably&#44; COPD was correlated with a lower risk of AI in our study&#46; In a similar line&#44; Schauwvlieghe et al&#46;<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">3</span></a> found that COPD was not an independent risk factor for IAPA &#40;OR&#58; 1&#46;10&#44; 95&#37; CI&#58; 0&#46;53&#8211;2&#46;26&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;80&#41;&#46; Several studies describe COPD as a risk factor for aspergillosis&#44; especially in patients receiving chronic corticosteroid treatment&#46;<a class="elsevierStyleCrossRefs" href="#bib0245"><span class="elsevierStyleSup">19&#44;26&#8211;29</span></a> In our population&#44; the proportion of patients with COPD was similar in the group with and without AI&#44; and within COPD patients&#44; the use of corticosteroids was similar in patients with and without aspergillosis &#40;1&#46;8&#37; vs 1&#46;5&#37; respectively&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;8&#44; data not shown&#41;&#46;</p><p id="par0135" class="elsevierStylePara elsevierViewall">The association observed between nosocomial-acquired influenza and AI could be explained by the increased risk of hospitalized patients to acquire influenza as an expression of a subclinical condition of impaired immunity or immuno-paralysis associated with the serious processes that led to hospitalization&#44; something that facilitates the development of opportunistic infections&#46;<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">30</span></a> In this regard&#44; patients with AI were admitted in the ICU with a higher median of hospital days previous admission than patients without AI&#44; but these differences were no significant in the multivariate analysis&#46;</p><p id="par0140" class="elsevierStylePara elsevierViewall">Finally&#44; AI patients presented three times greater ICU-mortality than those in whom AI was not present &#40;59&#37; vs 21&#37;&#41;&#46; This high mortality coincides with the one published by Schauwvlieghe et al&#46;<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">3</span></a> with a mortality of 45&#37; in patients with aspergillosis compared to 20&#37; in the rest of the cohort patients&#44; and with the study published by Vanderbeke et al&#46;<a class="elsevierStyleCrossRef" href="#bib0260"><span class="elsevierStyleSup">22</span></a> who observed a mortality of 57&#37; in patients with aspergillosis and influenza infection&#46;</p><p id="par0145" class="elsevierStylePara elsevierViewall">The main strength of our study is that it is a homogeneous&#44; multicenter cohort with a numerous number of critically ill patients with confirmed influenza infection&#44; which allows the results to be generalizable&#46; Nonetheless&#44; we must recognize several limitations&#46; First&#44; it was a secondary analysis of an observational study&#44; and although patients have been included consecutively&#44; we cannot rule out possible biases in reporting the cases&#59; yet&#44; the high number of patients and the rigorous statistical analysis performed minimize these risks and make the results generalizable&#46; Another major limitation is the fact that we cannot confirm proven PA diagnosis in most of our patients because we only have microbiological isolation and imaging tests&#59; furthermore&#44; we do not have information about in how many of our patients a bronchoscopy had been performed and diagnosis was made by BAL&#46; In this way&#44; there is the possibility that &#8220;colonized&#8221; patients may have been included&#46; However&#44; the low incidence of AI and high associated mortality make this scenario unlikely&#46; Moreover&#44; these are real-world data&#44; because this is what clinician do during the current clinical practice&#44; which makes our results very important for patient care and clinical practice&#46; Another limitation could be related to the low number of patients with AI included&#46; Despite this&#44; the observed differences in mortality have achieved significance with a post-hoc calculated statistical power of 89&#37;&#46; Finally&#44; it is possible that the low incidence observed is due to the lack of an active search investigation through the determination of galactomannan in BAL&#46; Although we cannot rule out this possibility&#44; this technique is not available in all hospitals in Spain&#46;</p></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0170">Conclusions</span><p id="par0150" class="elsevierStylePara elsevierViewall">Due to the low incidence of AI in our population of critically ill patients with influenza infection&#44; the extensive use of empirical antifungal treatment in all patients may not be justified&#46; In moderate-high risk patients&#44; the active search for <span class="elsevierStyleItalic">Aspergillus</span> spp&#46; should be systematically implemented&#46;</p></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0175">Funding</span><p id="par0155" class="elsevierStylePara elsevierViewall">This research received no external funding&#46; This study was supported by the Spanish Intensive Care Society &#40;<span class="elsevierStyleGrantSponsor" id="gs1">SEMICYUC</span>&#41; and <span class="elsevierStyleGrantSponsor" id="gs2">Ricardo Barri Casanovas Foundation</span> &#40;Alejandro Rodr&#237;guez&#41;&#46; The study sponsors have no role in the study design&#44; data collection&#44; data analysis&#44; data interpretation&#44; or writing of the report&#46;</p></span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0180">Author contributions</span><p id="par0160" class="elsevierStylePara elsevierViewall">L&#46;C&#46;&#44; X&#46;D&#46;&#44; I&#46;M&#46;-L&#46;&#44; M&#46;B&#46;&#44; L&#46;F&#46;R&#46; and A&#46;R&#46; designed the study&#44; design of statistical analyses&#44; and data analysis&#46; All authors except G&#46;Q&#46;&#44; J&#46;P&#44; L&#46;F&#46;R&#46; and J&#46;J&#46;G&#46; contributed to the patient&#39;s data for the general database&#46; L&#46;C&#46;&#44; X&#46;D&#46;&#44; I&#44;M-L&#46;&#44; M&#46;B&#46;&#44; F&#46;G&#46;-B&#46;&#44; C&#46;S&#46;&#44; E&#46;P&#46;&#44; E&#46;D&#46;&#44; S&#46;T&#46;&#44; J&#46;P&#46;&#44; G&#46;Q&#46;&#44; J&#46;M-C&#46;&#44; L&#46;F&#46;R&#46;&#44; J&#46;S&#46;-V&#46;&#44; M&#46;B-S&#46;&#44; R&#46;Z&#46;&#44; J&#46;J&#46;G&#46;&#46;&#44; A&#46;R&#46; contributed to critical examination of the paper for important intellectual content and approval of the final manuscript&#46; All authors have read and agreed to the published version of the manuscript&#46;</p></span><span id="sec0085" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0185">Conflicts of interest</span><p id="par0165" class="elsevierStylePara elsevierViewall">The authors declare that they have no conflict of interest&#46;</p></span></span>"
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        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Objective</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">To determine the incidence and impact of <span class="elsevierStyleItalic">Aspergillus</span> spp&#46; isolation &#40;AI&#41; on ICU mortality in critically ill patients with severe influenza pneumonia during the first 24<span class="elsevierStyleHsp" style=""></span>h of admission&#46;</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Design</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Secondary analysis of an observational and prospective cohort study&#46;</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Setting</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">ICUs voluntary participating in the Spanish severe Influenza pneumonia registry&#44; between June 2009 and June 2019&#46;</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Patients</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Consecutive patients admitted to the ICU with diagnosis of severe influenza pneumonia&#44; confirmed by real-time polymerase chain reaction&#46;</p></span> <span id="abst0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Interventions</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">None&#46;</p></span> <span id="abst0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Main variables of interest</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Incidence of AI in respiratory samples&#46; Demographic variables&#44; comorbidities&#44; need for mechanical ventilation and the presence of shock according at admission&#46; Acute Physiology and Chronic Health Evaluation II &#40;APACHE II&#41; scale calculated on ICU admission&#46;</p></span> <span id="abst0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Results</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">3702 patients were analyzed in this study&#46; AI incidence was 1&#46;13&#37; &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>42&#41;&#46; Hematological malignancies &#40;OR 4&#46;39&#44; 95&#37; CI 1&#46;92&#8211;10&#46;04&#41;&#59; HIV &#40;OR 3&#46;83&#44; 95&#37; CI 1&#46;08&#8211;13&#46;63&#41;&#44; and other immunosuppression situations &#40;OR 4&#46;87&#44; 95&#37; CI 1&#46;99&#8211;11&#46;87&#41; were factors independently associated with the presence of <span class="elsevierStyleItalic">Aspergillus</span> spp&#46; The automatic CHAID decision tree showed that hematologic disease with an incidence of 3&#46;3&#37; was the most closely AI related variable&#46; Hematological disease &#40;OR 2&#46;62 95&#37; CI 1&#46;95&#8211;3&#46;51&#41;&#44; immunosuppression &#40;OR 2&#46;05 95&#37; CI 1&#46;46&#8211;2&#46;88&#41; and AI &#40;OR 3&#46;24&#44; 95&#37; CI 1&#46;60&#8211;6&#46;53&#41; were variables independently associated with ICU mortality&#46;</p></span> <span id="abst0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Conclusions</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">Empirical antifungal treatment in our population may only be justified in immunocompromised patients&#46; In moderate-high risk cases&#44; active search for <span class="elsevierStyleItalic">Aspergillus</span> spp&#46; should be implemented&#46;</p></span>"
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        "resumen" => "<span id="abst0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Objetivo</span><p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Determinar la incidencia y el impacto sobre la mortalidad del aislamiento de <span class="elsevierStyleItalic">Aspergillus</span> spp&#46; &#40;AI&#41; en paciente cr&#237;ticos con neumon&#237;a por influenza en las primeras 24<span class="elsevierStyleHsp" style=""></span>h de ingreso&#46;</p></span> <span id="abst0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Dise&#241;o</span><p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">An&#225;lisis secundario de estudio de cohortes observacional y prospectivo&#46;</p></span> <span id="abst0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">&#193;mbito</span><p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">Unidades de cuidados intensivos &#40;UCI&#41; participantes de forma voluntaria en el registro espa&#241;ol de neumon&#237;a por influenza grave&#44; desde junio de 2009 hasta junio de 2019&#46;</p></span> <span id="abst0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Pacientes</span><p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">Pacientes consecutivos con diagn&#243;stico de neumon&#237;a grave por influenza&#44; confirmado por prueba de reacci&#243;n en cadena de la polimerasa&#46;</p></span> <span id="abst0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Intervenciones</span><p id="spar0065" class="elsevierStyleSimplePara elsevierViewall">Ninguna&#46;</p></span> <span id="abst0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Variables principales</span><p id="spar0070" class="elsevierStyleSimplePara elsevierViewall">Incidencia de AI<span class="elsevierStyleItalic">&#46;</span> Variables demogr&#225;ficas&#44; comorbilidades&#44; necesidad de ventilaci&#243;n mec&#225;nica y presencia de <span class="elsevierStyleItalic">shock</span> al ingreso&#46; APACHE II&#46;</p></span> <span id="abst0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Resultados</span><p id="spar0075" class="elsevierStyleSimplePara elsevierViewall">Se analizaron 3&#46;702 pacientes&#46; La incidencia de AI fue del 1&#44;13&#37; &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>42&#41;&#46; Las neoplasias hematol&#243;gicas &#40;OR&#58; 4&#44;39&#59; IC 95&#37;&#58; 1&#44;92-10&#44;04&#41;&#59; VIH &#40;OR&#58; 3&#44;83&#59; IC 95&#37;&#58; 1&#44;08-13&#44;63&#41; y otras situaciones de inmunosupresi&#243;n &#40;OR&#58; 4&#44;87&#59; IC 95&#37;&#58; 1&#44;99-11&#44;87&#41; fueron variables que se asociaron de forma independiente con AI&#46; El &#225;rbol de decisi&#243;n de CHAID mostr&#243; que la variable neoplasias hematol&#243;gicas era la m&#225;s relacionada con la variable <span class="elsevierStyleItalic">Aspergillus</span> spp&#46; con una incidencia del 3&#44;3&#37;&#46; Neoplasias hematol&#243;gicas &#40;OR&#58; 2&#44;62&#59; IC 95&#37;&#58; 1&#44;95-3&#44;51&#41;&#44; inmunosupresi&#243;n &#40;OR&#58; 2&#44;05&#59; IC 95&#37;&#58; 1&#44;46-2&#44;88&#41; y AI &#40;OR&#58; 3&#44;24&#59; IC 95&#37;&#58; 1&#44;60-6&#44;53&#41; se asociaron de forma independiente con mayor mortalidad en la UCI&#46;</p></span> <span id="abst0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Conclusiones</span><p id="spar0080" class="elsevierStyleSimplePara elsevierViewall">El tratamiento antif&#250;ngico emp&#237;rico en nuestra poblaci&#243;n estar&#237;a justificado en los pacientes con inmunosupresi&#243;n&#46; En los pacientes con riesgo moderado-grave&#44; la b&#250;squeda activa de <span class="elsevierStyleItalic">Aspergillus</span> spp&#46; deber&#237;a implementarse&#46;</p></span>"
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                  \t\t\t\t">33 &#40;78&#46;6&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t"><span class="elsevierStyleItalic">APACHE II &#8211; mean &#40;SD&#41;</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">17&#46;0 &#40;7&#46;9&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">16&#46;9 &#40;7&#46;9&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleItalic">Mechanical ventilation &#8211; n &#40;&#37;&#41;</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">2936 &#40;79&#46;3&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">2984 &#40;79&#46;1&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">42 &#40;100&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
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                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t"><span class="elsevierStyleItalic">Vasoactive drugs &#8211; n &#40;&#37;&#41;</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t">1899 &#40;51&#46;3&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t">1868 &#40;51&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">31 &#40;74&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">&#60;0&#46;05&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t"><span class="elsevierStyleItalic">RRT &#8211; n &#40;&#37;&#41;</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t">375 &#40;10&#46;1&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">368 &#40;10&#46;1&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">7 &#40;16&#46;7&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">0&#46;19&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t"><span class="elsevierStyleItalic">CRP&#44; mg&#47;dl &#8211; mean &#40;SD&#41;</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">29 &#40;13&#46;7&#8211;100&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">29&#46;0 &#40;13&#46;2&#8211;100&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">35&#46;5 &#40;19&#46;6&#8211;186&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t">0&#46;44&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t"><span class="elsevierStyleItalic">PCT&#44; ng&#47;ml &#8211; median &#40;IQR&#41;</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">0&#46;7 &#40;0&#46;2&#8211;4&#46;3&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">1&#46;6 &#40;0&#46;5&#8211;4&#46;4&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">0&#46;25&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t">8 &#40;19&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t  " colspan="5" align="left" valign="\n
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                  \t\t\t\t"><span class="elsevierStyleItalic">Type of influenza virus &#8211; n &#40;&#37;&#41;</span></td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>A H1N1&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">2620 &#40;70&#46;8&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">2590 &#40;70&#46;8&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">30 &#40;71&#46;5&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">764 &#40;20&#46;6&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">8 &#40;19&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleItalic">Comorbidities &#8211; n &#40;&#37;&#41;</span></td></tr><tr title="table-row"><td class="td-with-role" title="\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Pregnancy&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">2 &#40;4&#46;8&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Obesity&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">1165 &#40;31&#46;8&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">106 &#40;2&#46;9&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">0&#46;63&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Autoimmune disease&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">147 &#40;4&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">2 &#40;4&#46;8&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>HIV positive&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">86 &#40;2&#46;3&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">83 &#40;2&#46;3&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">3 &#40;7&#46;1&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">0&#46;07&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Hematological disease&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">272 &#40;7&#46;3&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">263 &#40;7&#46;2&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">9 &#40;21&#46;4&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">&#60;0&#46;05&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Other IS&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">193 &#40;5&#46;2&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">186 &#40;5&#46;1&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">7 &#40;16&#46;6&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">&#60;0&#46;05&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t">Asthma &#8211; <span class="elsevierStyleItalic">n</span> &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
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