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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Invasive pneumococcal disease &#40;IPD&#41; continues to cause significant morbidity and mortality in the paediatric population of Spain&#44; even after the introduction in our country of the pneumococcal conjugate vaccine&#46;<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">1</span></a> The incidence of IPD in children under 5 years in Spain ranges between 16&#46;8 &#40;2012&#41; and 12&#46;3 &#40;2015&#41; per 100<span class="elsevierStyleHsp" style=""></span>000 inhabitants&#46;<a class="elsevierStyleCrossRefs" href="#bib0100"><span class="elsevierStyleSup">1&#44;2</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">In some cases&#44; it requires admission to the paediatric intensive care unit &#40;PICU&#41; due to the severity of the symptoms&#46; Some forms of IPD&#44; such as sepsis or meningitis&#44; require intensive care from onset&#44; with management based on the continuous monitoring and intensive treatment that these forms require once they are diagnosed&#46; Other forms&#44; such as complicated pneumonia&#44; do not always require admission to the PICU to be cured and could be managed initially in a hospital without paediatric intensive care services&#46;<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">3</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">The aim of our study was to analyse the epidemiological&#44; microbiological and clinical characteristics of cases of IPD potentially requiring admission to the PICU&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Methods</span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Study design</span><p id="par0020" class="elsevierStylePara elsevierViewall">We conducted a prospective study in children aged 2 to 59 months given a diagnosis of IPD between January 1&#44; 2012 and June 30&#44; 2016 managed in 3 children&#39;s hospitals in Barcelona&#44; Spain &#40;Hospital Sant Joan de D&#233;u&#44; Hospital Materno-Infantil Vall d&#8217;Hebron and Hospital HM Nens&#41; with an estimated cumulative catchment population under 5 years of 116<span class="elsevierStyleHsp" style=""></span>279 inhabitants &#40;30&#46;4&#37; of the total population aged &#60;5 years in Catalonia&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">2</span></a> The first 2 hospitals have a PICU and are the 2 referral PICUs in Catalonia&#44; although there are other PICUs in the region&#46;</p><p id="par0025" class="elsevierStylePara elsevierViewall">We defined IPD as clinical manifestations of infection in addition to isolation of <span class="elsevierStyleItalic">Streptococcus pneumoniae</span> or detection of DNA corresponding to the <span class="elsevierStyleItalic">LytA</span> gene and an additional capsule gene by reverse transcription polymerase chain reaction &#40;RT-PCR&#41; in a sample collected from a normally sterile site&#46;</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Demographic&#44; clinical and epidemiological variables</span><p id="par0030" class="elsevierStylePara elsevierViewall">For each case of IPD&#44; we collected data on the following demographic&#44; clinical and epidemiological variables&#58; age&#44; sex&#44; date of birth&#44; date of onset&#44; date of hospital admission&#44; form of IPD &#40;meningitis&#44; septic shock&#44; complicated or uncomplicated pneumonia&#44; occult bacteraemia and other&#44; less frequent forms&#41;&#44; complications&#44; admission to PICU and length of stay&#44; presence of medical risk factors &#40;sickle cell anaemia&#44; congenital or acquired asplenia&#44; infection by human immunodeficiency virus&#44; cochlear implant&#44; severe congenital immunodeficiency requiring treatment&#44; chronic heart disease requiring treatment or surgically corrected&#44; chronic respiratory disease including asthma treated with high-dose steroids &#40;methylprednisolone at a dose &#62;1<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#47;day for longer than 1 month&#41;&#44; cerebrospinal fluid fistula&#44; chronic renal failure including nephrotic syndrome requiring dialysis&#44; immunosuppressive therapy or radiotherapy in the past 6 months&#44; solid organ or haematopoietic stem cell transplantation&#44; and insulin-dependent diabetes mellitus&#41;&#44; date of discharge and outcome at discharge &#40;discharge without sequelae&#44; discharge with sequelae&#44; death&#41;&#46; We considered that pneumonia was complicated in case of lung consolidation with more than one of the following&#58; pleural effusion greater than 10<span class="elsevierStyleHsp" style=""></span>mm&#44; loculated pleural effusion&#44; parapneumonic empyema&#44; necrotising pneumonia or pulmonary abscess&#46; We assessed for the presence of sequelae at 6 months from diagnosis&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Identification&#44; serotyping and classification of <span class="elsevierStyleItalic">S&#46; pneumoniae</span></span><p id="par0035" class="elsevierStylePara elsevierViewall">Strains isolated from culture were serotyped by means of the Quellung reaction or a dot blot assay in the Pneumococcus Reference Laboratory of the Centro Nacional de Microbiolog&#237;a &#40;National Centre of Microbiology&#41; in Majadahonda &#40;Madrid&#44; Spain&#41;&#46; In patients in which the pneumococcal strain could not be isolated from culture&#44; serotyping was performed by means of RT-PCR&#44; which allows detection of 43 different serotypes&#47;serogroups with the multilocus sequence typing &#40;MLST&#41; method&#44; which is recognised at the international level&#46;</p><p id="par0040" class="elsevierStylePara elsevierViewall">Since PCR does not differentiate between serotypes 6A and 6<span class="elsevierStyleSmallCaps">C</span>&#44; 7F and 7A&#44; 9V&#44; 9A and 9N and 19F&#44; 19B and 19C&#44; we only considered serotypes 6A&#44; 7F&#44; 9V and 19F as vaccine serotypes once their identification was confirmed by the Pneumococcus Reference Laboratory in Majadahonda&#46;<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">2</span></a></p><p id="par0045" class="elsevierStylePara elsevierViewall">Genotyping from samples was performed at the Molecular Biology Laboratory of the Hospital Sant Joan de D&#233;u with the MLST method&#46; We identified allelic profiles and sequence types with the software available at <a href="http://pubmlst.org/spneumoniae/">http&#58;&#47;&#47;pubmlst&#46;org&#47;spneumoniae&#47;</a>&#46; We analysed sequence types and assigned specific clonal complexes using the eBURST algorithm&#46;</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Criteria for admission to the PICU</span><p id="par0050" class="elsevierStylePara elsevierViewall">The children admitted to the PICU met all or some of the following criteria&#58; IPD with severe haemodynamic instability that did not improve with administration of 1 or 2 boluses of fluids&#59; diagnosis of meningitis&#59; development of acute respiratory distress syndrome defined as a ratio of arterial oxygen partial pressure &#40;PaO2&#41; to fractional inspired oxygen &#40;FiO<span class="elsevierStyleInf">2</span>&#41; of 200 to 250&#59; need for invasive or non-invasive mechanical ventilation&#59; signs of acute renal failure &#40;2-fold or greater increase in serum creatinine relative to baseline over a 12&#8211;24<span class="elsevierStyleHsp" style=""></span>h interval&#41;&#59; disseminated intravascular coagulation&#59; Glasgow coma scale score of less than 8&#46;<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">3</span></a></p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Vaccination against pneumococcus</span><p id="par0055" class="elsevierStylePara elsevierViewall">We obtained the vaccination status of each patient with IPD from the official vaccination history card&#44; the records of the public or private primary care centre that managed the child routinely or the patient health records&#46; We defined correct vaccination as having received every dose of pneumococcal 13-valent conjugate vaccine &#40;PCV13&#41; scheduled up to the patient&#39;s age as established by the summary of product characteristics&#46;<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">4</span></a></p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Statistical analysis</span><p id="par0060" class="elsevierStylePara elsevierViewall">We assessed the association between categorical variables with the <span class="elsevierStyleItalic">&#967;</span><span class="elsevierStyleSup">2</span> test or the Fisher exact test&#44; and the association between continuous variables with the Student <span class="elsevierStyleItalic">t</span> test&#46; To estimate the strength of the association between the variables under study and admission to the PICU&#44; we calculated odds ratios &#40;ORs&#41; with the corresponding 95&#37; confidence intervals &#40;CIs&#41;&#46; We defined statistical significance as a <span class="elsevierStyleItalic">P</span>-value of &#46;05&#46; All tests were two-tailed&#46;</p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Ethical considerations</span><p id="par0065" class="elsevierStylePara elsevierViewall">The study was approved by the ethics committees of the 3 participating hospitals&#46; The guardians of the patient signed an informed consent document stating that they understood the study&#44; accepted to participate and had the right to withdraw at any time&#46;</p></span></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Results</span><p id="par0070" class="elsevierStylePara elsevierViewall">The study included 263 patients with IPD &#40;155 male and 108 female&#41;&#44; with a mean age of 45 months &#40;standard deviation &#91;SD&#93;&#44; 37&#46;1&#41;&#44; out of who 50 &#40;19&#37;&#41; required admission to the PICU at some point in the course of disease &#40;Group 1&#41;&#46; The remaining 213 patients did not require admission to the PICU &#40;Group 2&#41;&#46; The incidence of IPD peaked in February &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>54&#59; 20&#46;5&#37;&#41; and March &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>44&#59; 16&#46;7&#37;&#41;&#44; while admission to the PICU peaked in March &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>10&#59; 20&#37;&#41; and December &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>7&#59; 14&#37;&#41; &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>A&#41;&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0075" class="elsevierStylePara elsevierViewall">The length of stay was significantly longer in patients that required admission to the PICU &#40;19&#46;8<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>12&#46;5 days&#41; compared to those that did not &#40;9&#46;6<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>5&#46;8 days&#41; &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>&#46;001&#41;&#46; We found that 46&#46;7&#37; of patients with underlying disease required admission to the PICU compared to 17&#46;3 of patients that were previously healthy&#46; The ratio of the number of patients admitted to the PICU to the number not admitted was 4&#46;17 times greater in patients with underlying disease compared to previously healthy patients&#44; and this association was statistically significant &#40;OR&#44; 4&#46;17&#59; 95&#37; CI&#44; 1&#46;44&#8211;12&#46;12&#41;&#46;</p><p id="par0080" class="elsevierStylePara elsevierViewall">The forms of IPD found in the total sample were &#40;<span class="elsevierStyleItalic">n</span>&#59; &#37;&#41;&#58; complicated pneumonia &#40;152&#59; 57&#46;4&#37;&#41;&#44; uncomplicated pneumonia &#40;43&#59; 16&#46;3&#37;&#41;&#44; occult bacteraemia &#40;25&#59; 9&#46;5&#37;&#41;&#44; meningitis &#40;19&#59; 7&#46;2&#37;&#41;&#44; septic shock &#40;7&#59; 2&#46;7&#37;&#41;&#44; mastoiditis &#40;7&#59; 2&#46;7&#37;&#41;&#44; osteoarticular infection &#40;7&#59; 2&#46;7&#37;&#41;&#44; orbital cellulitis &#40;2&#59; 0&#46;8&#37;&#41;&#44; peritonitis &#40;1&#41; and pancreatitis &#40;1&#41;&#46; In group 1&#44; the patients admitted to the PICU included 100&#37; of patients with septic shock &#40;OR&#44; 5&#46;95&#59; 95&#37; CI&#44; 4&#46;53&#8211;7&#46;82&#41;&#44; 84&#46;2&#37; of patients with meningitis &#40;OR&#44; 32&#46;94&#59; 95&#37; CI&#44; 9&#46;11&#8211;119&#46;10&#41; and 15&#46;2&#37; of patients with complicated pneumonia &#40;OR&#44; 0&#46;57&#59; 95&#37; CI&#44; 0&#46;30&#8211;1&#46;50&#41;&#44; although in the latter case the association with PICU admission was not statistically significant&#46; Group 2&#44; composed of the patients that did not require PICU admission&#44; included 95&#37; of the patients with uncomplicated &#40;OR&#44; 0&#46;18&#59; 95&#37; CI&#44; 0&#46;04&#8211;0&#46;75&#41; &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a> and <a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>B&#41;&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0085" class="elsevierStylePara elsevierViewall">In both groups 1 and 2&#44; 64&#46;4&#37; of patients with IPD experienced some form of complication&#59; 57&#46;8&#37; were respiratory complications and 5&#46;3&#37; neurologic complications&#46; Of the patients with neurologic complications during the acute phase&#44; 85&#46;7&#37; required admission to the PICU &#40;OR&#44; 33&#46;3&#59; 95&#37; CI&#44; 7&#46;17&#8211;154&#46;8&#41;&#44; as did 15&#46;8&#37; of the patients with respiratory complications &#40;OR&#44; 0&#46;613&#59; 95&#37; CI&#44; 0&#46;33&#8211;1&#46;14&#41; &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>C&#41;&#46;</p><p id="par0090" class="elsevierStylePara elsevierViewall">Of the 260 patients with IPD for who follow-up data were available&#44; 85&#46;5&#37; were free of sequelae at 6 months&#46; Two patients died and 1 did not attend the follow-up visit&#46; Out of the patients with immediate sequelae&#44; 22 &#40;8&#46;5&#37;&#41; had respiratory sequelae and 8 &#40;3&#46;1&#37;&#41; neurologic sequelae &#40;including 2 patients with hearing loss&#41;&#59; 1 patient had high blood pressure&#44; 1 required a radical mastoidectomy and 1 had cavernous sinus thrombosis&#46; In group 1&#44; 14&#46;3&#37; of patients developed neurologic sequelae &#40;OR&#44; 37&#46;1&#59; 95&#37; CI&#44; 4&#46;4&#8211;309-9&#41;&#44; followed in frequency by respiratory sequelae in 10&#46;2&#37; &#40;OR&#44; 1&#46;4&#59; 95&#37; CI&#44; 0&#46;48&#8211;3&#46;93&#41; &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>D&#41;&#46;</p><p id="par0095" class="elsevierStylePara elsevierViewall">Of all patients with IPD&#44; 84&#46;8&#37; &#40;223&#47;263&#41; had not received antibiotherapy at the outpatient level before admission&#44; and 20&#46;6&#37; of these subset of patients &#40;46&#47;223&#41; belonged to group 1 &#40;OR&#44; 0&#46;43&#59; 95&#37; CI&#44; 0&#46;145&#8211;1&#46;26&#59; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;115&#41;&#46;</p><p id="par0100" class="elsevierStylePara elsevierViewall">We found that 50&#46;4&#37; &#40;132&#47;263&#41; of patients&#44; without differences between groups&#44; had received at least 1 dose of pneumococcal conjugate vaccine&#46; Only 28&#46;1&#37; were correctly vaccinated for their age &#40;8&#46;7&#37; with PCV7&#59; 2&#46;3&#37; with PVC10 and17&#46;1&#37; with PCV13&#41;&#46; We did not find an association between the need for admission to the PICU &#40;group 1&#41; and complete PCV13 vaccination status &#40;OR&#44; 0&#46;48&#59; 95&#37; CI&#44; 0&#46;18&#8211;1&#46;3&#41; &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;135&#41;&#46;</p><p id="par0105" class="elsevierStylePara elsevierViewall">The serotypes identified most frequently in both groups were serotype 3 &#40;53 &#91;20&#46;2&#37;&#93;&#44; of who 17&#37; required PICU admission&#41;&#44; serotype 1 &#40;48 &#91;18&#46;3&#37;&#93;&#44; of who 12&#46;5&#37; required PICU admission&#41;&#44; other nonvaccine serotypes &#40;33 &#91;12&#46;5&#37;&#93;&#44; of who 21&#37; required PICU admission&#41;&#44; serotype 19A &#40;17&#59; 6&#46;5&#37;&#44; of who 23&#37; required PICU admission&#41; and serotype 14 &#40;15 &#91;5&#46;7&#37;&#93;&#44; of who 20&#37; required PICU admission&#41;&#46; The serotypes identified most frequently in patients of group 1 were &#40;<span class="elsevierStyleItalic">n</span>&#44; &#37;&#41;&#58; serotype 3 &#40;9&#59; 18&#37;&#41;&#44; other nonvaccine serotypes &#40;7&#59; 14&#37;&#41;&#44; serotype 1 &#40;6&#59; 12&#37;&#41; and serotype 19A &#40;4&#59; 8&#37;&#41;&#46; The most frequent nonvaccine serotypes in group 1 were serotypes 10A &#40;2&#59; 4&#37;&#41; and 11 &#40;2&#59; 4&#37;&#41; &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>&#41;&#46; There was only 1 case of vaccine failure in this group&#44; corresponding to a patient with infection by serotype 3&#46; When it came to genotyping&#44; the only salient finding in group 1 was detection of sequence type 306&#44; corresponding to serotype 1&#44; in 4&#47;6 cases&#59; the rest of sequence types and clonal complexes varied and were not associated significantly with PICU admission&#46;</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">Discussion</span><p id="par0110" class="elsevierStylePara elsevierViewall">Admission to the PICU is a possible development in the context of IPD&#44; so the exploration of the epidemiological&#44; microbiological and clinical factors may be associated with an increased likelihood of admission to the PICU is a relevant pursuit&#46; In our study&#44; we identified factors associated with an increased probability of admission to the PICU&#44; such as age less than 1 year at the time of diagnosis&#44; the presence of underlying disease that increases the risk of IPD&#44; specific presentations of IPD such as septic shock or meningitis and the months of the year corresponding to seasonal viral disease outbreaks&#46;</p><p id="par0115" class="elsevierStylePara elsevierViewall">The two seasonal peaks in the incidence of IPD and the peak in the proportion of patients with IPD requiring PICU admission coincided with the annual outbreaks of bronchiolitis due to respiratory syncytial virus &#40;RSV&#41; and influenza&#44; as described in previous studies&#46;<a class="elsevierStyleCrossRefs" href="#bib0120"><span class="elsevierStyleSup">5&#8211;9</span></a> However&#44; while the incidence of IPD peaked in February and March &#40;and the influenza outbreak occurred between week 50 of 2013 and week 12 of 2014<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">10</span></a>&#41;&#44; the months corresponding to the highest proportion of IPD cases requiring PICU admission were November and December &#40;overlapping with the RSV season that happens between week 40 of one year and week 4 of the following year<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">10</span></a>&#41;&#46; This could be explained by different factors&#44; such as the lower age of patients with bronchiolitis&#44; the virulence of the virus involved in the RSV or flu season&#44; and the previous health of the patient&#46;<a class="elsevierStyleCrossRefs" href="#bib0125"><span class="elsevierStyleSup">6&#44;7</span></a></p><p id="par0120" class="elsevierStylePara elsevierViewall">Outpatient management with antibiotherapy previous to hospital admission does not have a protective effect against admission to the PICU&#44; as we found in our series and in reviewing the work of other authors&#46;<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">11</span></a></p><p id="par0125" class="elsevierStylePara elsevierViewall">The total length of stay was greater in patients admitted to the PICU&#44; which was consistent with the findings of previous studies&#46;<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">12</span></a> When it came to the forms of IPD that required admission to the PICU&#44; we found that the only feature present in 100&#37; of the patients admitted to the PICU was haemodynamic instability&#46; Although a diagnosis of meningitis was in itself a criterion for admission to the PICU&#44; it was not always made at the outset and patients with a discharge diagnosis of meningitis that were not admitted to the PICU had favourable outcomes&#46; This was because 39&#46;5&#37; of the patients with meningitis admitted to the PICU had complications during the acute phase&#44; as was observed in other studies&#44; such as the one published by Casado et al&#46;<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">11</span></a> Most children with IPD admitted to the PICU recovered and were free of sequelae&#46; The most frequent sequelae were neurologic&#44; followed by respiratory sequelae&#46; Only 15&#46;2&#37; of patients with complicated pneumonia with pleural effusion or empyema required admission to the PICU&#44; which demonstrates that these patients may be managed in a hospital without an intensive care unit under close monitoring&#46;<a class="elsevierStyleCrossRefs" href="#bib0150"><span class="elsevierStyleSup">11&#44;13</span></a></p><p id="par0130" class="elsevierStylePara elsevierViewall">Although the most prevalent serotypes &#40;especially 19A&#41; are covered by the PCV13&#44; 11&#46;8&#37; of the patients with complete PCV13 vaccination were admitted to the PICU compared to 18&#46;5&#37; of patients without complete vaccination &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;23&#41;&#44; a difference that was not statistically significant&#46; Thus&#44; in our study&#44; complete vaccination with PCV13 did not exhibit a protective effect as concerned admission to the PICU&#46; The only case of vaccine failure in a patient that required intensive care involved serotype 3&#44; against which the PCV13 proved to be less effective compared to other serotypes&#44; as found in previous studies&#46;<a class="elsevierStyleCrossRefs" href="#bib0165"><span class="elsevierStyleSup">14&#8211;16</span></a> Asner et al&#46;<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">16</span></a> reported vaccine failure in 26&#37; of patients that required admission to the PICU&#44; with many of these cases involving serotype 3&#46; We ought to mention 2 serotypes that are not included in the PCV13&#44; 10A and 11A&#44; which&#44; while infrequent among our patients&#44; are associated with a high proportion of PICU admission&#46; In a prospective study conducted in Switzerland that included 117 patients with IPD&#44; patients with meningitis&#44; especially those with infection by non-vaccine serotypes&#44; were most likely to require admission to the PICU&#46;<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">16</span></a></p><p id="par0135" class="elsevierStylePara elsevierViewall">When it came to the serotypes involved in IPD&#44; in our study serotype 3 was the one corresponding to the highest proportion of affected patients requiring admission to the PICU&#44; which may be attributable to the characteristics of this serotype&#44; which has capsule proteins resulting in greater virulence&#44;<a class="elsevierStyleCrossRefs" href="#bib0180"><span class="elsevierStyleSup">17&#44;18</span></a> and the lower efficacy of the PCV13 against this serotype&#44; described in the previous literature&#46;<a class="elsevierStyleCrossRefs" href="#bib0165"><span class="elsevierStyleSup">14&#44;17&#44;18</span></a> This was also the serotype most frequently associated with development of IPD and with vaccine failure in our study&#46;</p><p id="par0140" class="elsevierStylePara elsevierViewall">These results evince the need of ongoing surveillance of pneumococcal serotypes involved in IPD and their genotypes to have updated information on the aetiological agents of IPD in the local population at all times&#46;<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">19</span></a></p><p id="par0145" class="elsevierStylePara elsevierViewall">There are limitations to our study&#46; First of all&#44; the sample only included 30&#46;4&#37; of the population under 5 years in Catalonia&#44; as we only studied IPD in 3 of the hospitals in the region&#46; Secondly&#44; only 2 of the 3 participating hospitals had a PICU&#44; and while these 2 units are the referral PICUs in Catalonia&#44; there are other hospitals that manage patients with IPD&#46; Third of all&#44; there may have been biases associated with the documentation of clinical data in the health records&#44; and some pneumococcal strains were not analysed&#44; meaning the resulting information was not available for 100&#37; of the cases&#46; Lastly&#44; data collection in the last year included in the study period ended in June&#44; which means that the study did not include data corresponding to the bronchiolitis season of that year&#46;</p></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">Conclusions</span><p id="par0150" class="elsevierStylePara elsevierViewall">In our series&#44; the presence of septic shock and&#47;or neurologic involvement in the context of IPD was associated with admission to the PICU&#44; and the proportion of patients admitted to the PICU was higher in the group of patients with underlying disease&#46; The frequency of PICU admission increased during the annual bronchiolitis season&#46; Admission to the PICU was associated with a longer length of stay in hospital&#44; a higher prevalence of complications in the acute phase and a higher prevalence of sequelae&#44; mainly neurologic&#46; The most frequent serotypes involved in the group of patients admitted to the PICU were vaccine serotypes &#40;19A&#44; 14&#44; 3 and 1&#41;&#46; Admission to the PICU in the context of IPD is necessary in patients that develop septic shock or neurologic complications&#46; In case of complicated pneumonia&#44; it is possible to manage the patient in the paediatric ward under close monitoring&#46;</p></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0125">Funding</span><p id="par0155" class="elsevierStylePara elsevierViewall">National R&#38;D&#38; programme&#44; Instituto de Salud Carlos III-Vice Directorate General of Evaluation and Promotion of Research in Health Care&#46; Grant no&#46; <span class="elsevierStyleGrantNumber" refid="gs1">P111&#47;02081&#44; PI 11&#47;2345</span>&#59; European Regional Development Fund &#40;<span class="elsevierStyleGrantSponsor" id="gs1">ERDF</span>&#41; and Agencia de Gesti&#243;n de Ayudas Universitarias y de Investigaci&#243;n &#40;<span class="elsevierStyleGrantSponsor" id="gs2">AGAUR</span>&#41;&#46; Grant no&#46; <span class="elsevierStyleGrantNumber" refid="gs2">2017 SGR 1342</span>&#46;</p></span><span id="sec1065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect1125">Declaration of Competing Interest</span><p id="par1155" class="elsevierStylePara elsevierViewall">No conflicts of interest&#46;</p></span></span>"
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        "titulo" => "Abstract"
        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Introduction</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Patients with invasive pneumococcal disease &#40;IPD&#41; may require admission into paediatric intensive care units &#40;PICU&#41;&#46; The aim of this study is to analyse the epidemiological&#44; clinical&#44; and microbiological characteristics associated with IPD that may require admission to the PICU&#46;</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Material and methods</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">A prospective study was conducted on cases of IPD diagnosed in three Paediatric Hospitals in Barcelona between January 2012 and June 2016&#46; An analysis was made of the associations between the admission to PICU and the epidemiological&#44; clinical&#44; and microbiological variables&#46;</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Results</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">A total of 263 cases with IPD were included&#44; of which 19&#37; &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>50&#41; required admission to PICU&#46; Patients with septic shock &#40;7&#59; 100&#37;&#41;&#44; meningitis &#40;16&#59; 84&#46;2&#37;&#41;&#44; and those with complicated pneumonia &#40;23&#59; 15&#46;2&#37;&#41; were admitted to the PICU&#46; The most frequent complications were pulmonary &#40;35&#46;2&#37;&#41; and neurological &#40;39&#46;5&#37;&#41;&#46; The ratio between admission and non-admission to PICU was 4&#46;7 times higher in subjects with an underlying disease&#46; The serotypes associated with PICU admission were 19A &#40;23&#37; of the total of this serotype&#41;&#44; serotype 14 &#40;20&#37;&#41;&#44; serotype 3 &#40;17&#37;&#41;&#44; and serotype 1 &#40;12&#46;5&#37;&#41;&#46;</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Conclusions</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">IPD required PICU admission in cases of septic shock and meningitis&#44; and less so with complicated pneumonia&#46; The percentage of admissions is greater in children with an underlying disease&#46; Admission into the PICU involves a longer stay&#44; complications during the acute phase&#44; as well as sequelae&#44; particularly neurological ones&#46; The serotypes of the patients that were admitted to PICU were predominantly vaccine serotypes&#46;</p></span>"
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        "resumen" => "<span id="abst0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Introducci&#243;n</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">La enfermedad neumoc&#243;cica invasora &#40;ENI&#41; puede requerir ingreso en la unidad de cuidados intensivos pedi&#225;tricos &#40;UCIP&#41;&#46; El objetivo de este trabajo es analizar las caracter&#237;sticas epidemiol&#243;gicas&#44; cl&#237;nicas y microbiol&#243;gicas asociadas a la ENI que predisponen el ingreso en la UCIP&#46;</p></span> <span id="abst0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Material y m&#233;todos</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Estudio prospectivo de casos diagnosticados con ENI en tres hospitales pedi&#225;tricos de Barcelona entre enero de 2012 y junio de 2016&#46; Se analizaron las asociaciones entre el ingreso en la UCIP y las variables epidemiol&#243;gicas&#44; cl&#237;nicas y microbiol&#243;gicas&#46;</p></span> <span id="abst0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Resultados</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Se incluyeron 263 casos con ENI&#46; El 19&#37; &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>50&#41; requiri&#243; ingreso en la UCIP&#46; El 100&#37; &#40;7&#41; de los pacientes con shock s&#233;ptico&#44; 84&#44;2&#37; &#40;16&#41; con meningitis y 15&#44;2&#37; &#40;23&#41; con neumon&#237;a complicada ingresaron en la UCIP&#46; Las complicaciones m&#225;s frecuentes fueron pulmonares &#40;35&#44;2&#37;&#41; y neurol&#243;gicas &#40;39&#44;5&#37;&#41;&#46; La raz&#243;n entre ingreso y no ingreso en la UCIP fue 4&#44;17 veces mayor en los sujetos con enfermedad de base&#46; Los serotipos asociados al ingreso en la UCIP fueron el 19A &#40;23&#37; del total de este serotipo&#41;&#44; el 14 &#40;20&#37;&#41;&#44; el 3 &#40;17&#37;&#41; y el serotipo 1 &#40;12&#44;5&#37;&#41;&#46;</p></span> <span id="abst0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Conclusiones</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">La ENI requiere ingreso en la UCIP en caso de shock s&#233;ptico y meningitis&#44; no as&#237;&#44; de entrada&#44; la neumon&#237;a complicada&#46; El porcentaje de ingresos es mayor en los ni&#241;os con enfermedad de base&#46; El ingreso en la UCIP conlleva una estancia m&#225;s prolongada&#44; as&#237; como complicaciones durante la fase aguda y secuelas&#44; sobre todo&#44; neurol&#243;gicas&#46; Los serotipos de los pacientes que ingresaron en la UCIP fueron&#44; predominantemente&#44; serotipos vacunales&#46;</p></span>"
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        "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as&#58; D&#237;az-Conradi A&#44; Garc&#237;a-Garc&#237;a JJ&#44; Gonz&#225;lez Peris S&#44; Fern&#225;ndez de Sevilla M&#44; Moraga Llop F&#44; Ventura PS&#44; et al&#46; Caracter&#237;sticas de los pacientes con enfermedad neumoc&#243;cica invasora que requieren ingreso en la unidad de cuidados intensivos&#46; An Pediatr &#40;Barc&#41;&#46; 2021&#59;94&#58;19&#8211;27&#46;</p>"
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        "nota" => "<p class="elsevierStyleNotepara" id="npar0015"><a class="elsevierStyleCrossRef" href="#sec0070">Appendix A</a> lists the members of the Group for the Study of Invasive Pneumococcal Disease in Catalonia &#40;Barcino Group&#41;&#46;</p>"
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        "nota" => "<p class="elsevierStyleNotepara" id="npar0010">Previous presentation&#58; This study was presented as an oral communication at the Annual Congress of the Asociaci&#243;n Espa&#241;ola de Pediatr&#237;a&#44; June 6&#8211;8&#44; 2019&#44; Burgos&#44; Spain&#46;</p>"
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            "apendice" => "<p id="par0160" class="elsevierStylePara elsevierViewall">Juan Jos&#233; Garc&#237;a Garc&#237;a&#44; Angela Dom&#237;nguez&#44; Fernando Moraga Llop&#44; Alvaro D&#237;az Conradi&#44; Mariona Fern&#225;ndez de Sevilla&#44; Sebasti&#224; Gonz&#225;lez Peris&#44; Pilar Ciruela&#44; Magda Campins&#44; Carmen Mu&#241;oz-Almagro&#44; Cristina Esteva&#44; Conchita Izquierdo&#44; Sonia Uriona&#44; Johanna Mart&#237;nez Osorio&#44; Anna Sol&#233; Ribalta&#44; Gemma Codina&#44; Nuria Soldevila y Llu&#237;s Salleras Sanmart&#237;&#46;</p>"
            "etiqueta" => "Appendix A"
            "titulo" => "Members of the Group for the Study of Invasive Pneumococcal Disease in Catalonia &#40;Estudio de la Enfermedad Invasora Neumoc&#243;cica en Catalu&#241;a&#44; Barcino&#41;"
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          "en" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Characteristics of patients based on whether or not they required admission to the paediatric intensive care unit &#40;PICU&#41;&#46; &#40;A&#41; Month of the year invasive pneumococcal disease was diagnosed&#46; &#40;B&#41; Clinical presentation&#46; &#40;C&#41; Complications&#46; &#40;D&#41; Sequelae&#46;</p>"
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Male&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">28 &#40;18&#46;1&#37;&#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">127 &#40;81&#46;9&#37;&#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">&#46;220&#46;639&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">0&#46;86 &#40;0&#46;46&#8211;1&#46;6&#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">0&#46;37 &#40;0&#46;12&#8211;1&#46;19&#41;&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
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Female&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">22 &#40;20&#46;4&#37;&#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">86 &#40;79&#46;6&#37;&#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="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&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="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&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="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="6" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></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
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Hospital length of stay in days</span>&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">9&#46;6<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>5&#46;8 &#40;8&#46;8&#8211;10&#46;4&#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">19&#46;8<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>12&#46;5 &#40;16&#46;2&#8211;23&#46;4&#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">&#60;&#46;001&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">&#8211;&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">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="6" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="6" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Underlying disease</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
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Yes&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">7 &#40;46&#46;7&#37;&#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">8 &#40;53&#46;3&#37;&#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">&#46;011&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">4&#46;17 &#40;1&#46;44&#8211;12&#46;12&#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">4&#46;97 &#40;0&#46;61&#8211;40&#46;64&#41;&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
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>No&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">43 &#40;17&#46;3&#37;&#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">205 &#40;82&#46;7&#37;&#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="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&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="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&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="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="6" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleVsp" style="height:1.0px"></span></td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="6" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleBold">Clinical presentation</span></td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="6" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Septic shock</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
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Yes&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">7 &#40;100&#37;&#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">0 &#40;0&#37;&#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">&#60;&#46;001&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">5&#46;95 &#40;4&#46;53&#8211;7&#46;82&#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="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&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
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>No&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">43 &#40;16&#46;8&#37;&#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">213 &#40;83&#46;2&#37;&#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="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&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="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&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="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="6" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="6" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Meningitis</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
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Yes&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">16 &#40;84&#46;2&#37;&#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">3 &#40;15&#46;8&#37;&#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">&#60;&#46;001&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">32&#46;94 &#40;9&#46;11&#8211;119&#46;10&#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">15&#46;27 &#40;2&#46;39&#8211;97&#46;67&#41;&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
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>No&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">34 &#40;13&#46;9&#37;&#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">210 &#40;86&#46;1&#37;&#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="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&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="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&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="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="6" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="6" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Complicated pneumonia</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
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Yes&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">23 &#40;15&#46;2&#37;&#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">128 &#40;84&#46;8&#37;&#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">&#46;07&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">0&#46;57 &#40;0&#46;304&#8211;1&#46;50&#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="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&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
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>No&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">27 &#40;24&#46;1&#37;&#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">85 &#40;75&#46;9&#37;&#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="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&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="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&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="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="6" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="6" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Uncomplicated pneumonia</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
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Yes&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">2 &#40;4&#46;7&#37;&#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">41 &#40;95&#46;3&#37;&#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">&#46;009&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">0&#46;18 &#40;0&#46;04&#8211;0&#46;75&#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">0&#46;21 &#40;0&#46;03&#8211;1&#46;41&#41;&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
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>No&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">48 &#40;21&#46;8&#37;&#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">172 &#40;78&#46;2&#37;&#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="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&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="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&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="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="6" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="6" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Bacteraemia</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
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Yes&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">1 &#40;4&#46;0&#37;&#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">24 &#40;96&#46;0&#37;&#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">&#46;081&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">0&#46;16 &#40;0&#46;02&#8211;1&#46;21&#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">0&#46;11 &#40;0&#46;01&#8211;1&#46;31&#41;&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
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>No&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">49 &#40;20&#46;6&#37;&#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">189 &#40;79&#46;4&#37;&#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="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&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="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&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="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="6" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="6" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Other presenting symptoms</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
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Yes&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">1 &#40;5&#46;6&#37;&#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">17 &#40;94&#46;4&#37;&#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">&#46;232&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">0&#46;24 &#40;0&#46;03&#8211;1&#46;81&#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="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&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
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>No&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">49 &#40;20&#37;&#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">196 &#40;80&#37;&#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="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&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="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&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="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="6" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="6" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Acute complications</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
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>None&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">12 &#40;12&#46;9&#37;&#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">81 &#40;87&#46;1&#37;&#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="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&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="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&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">Ref&#46;&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
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Neurologic&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">12 &#40;85&#46;7&#37;&#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">2 &#40;14&#46;3&#37;&#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">&#60;&#46;001&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">33&#46;3 &#40;7&#46;17&#8211;154&#46;8&#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&#46;53 &#40;0&#46;83&#8211;68&#46;23&#41;&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
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Respiratory&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">24 &#40;15&#46;8&#37;&#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">128 &#40;84&#46;2&#37;&#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">&#46;536&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">0&#46;613 &#40;0&#46;33&#8211;1&#46;14&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t">5 &#40;11&#46;1&#37;&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">0&#46;48 &#40;0&#46;18&#8211;1&#46;29&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Incomplete or unvaccinated&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">45 &#40;20&#46;6&#37;&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">172 &#40;79&#46;4&#37;&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
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          "en" => "<p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">Characteristics of patients with invasive pneumococcal disease&#44; compared based on the need for admission in the paediatric intensive care unit&#46;</p>"
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      "titulo" => "References"
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        0 => array:2 [
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                    0 => array:2 [
                      "titulo" => "Epidemiolog&#237;a de la enfermedad invasiva neumoc&#243;cica en Catalu&#241;a&#46; Reporte 2012-2016"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
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                            0 => "P&#46; Ciruela"
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              "identificador" => "bib0105"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Effectiveness of the 13-valent pneumococcal conjugate vaccine in preventing invasive pneumococcal disease in children aged 7-59 months&#46; A matched case-control study"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "A&#46; Dom&#237;nguez"
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                            2 => "S&#46; Hern&#225;ndez"
                            3 => "J&#46;J&#46; Garc&#237;a-Garc&#237;a"
                            4 => "N&#46; Soldevila"
                            5 => "C&#46; Izquierdo"
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                0 => array:2 [
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                      "titulo" => "Burden of disease caused by Streptococcus pneumoniae in children younger than 5 years&#58; global estimates"
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                            3 => "E&#46; Henkle"
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                            5 => "N&#46; McCall"
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                        "volumen" => "374"
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                        "paginaFinal" => "902"
                        "link" => array:1 [
                          0 => array:2 [
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                0 => array:2 [
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                      "titulo" => "Ficha t&#233;cnica o resumen de las caracter&#237;sticas de la vacuna antineumoc&#243;cica polisac&#225;rida conjugada &#40;13-valente&#44; adsorbida&#41; Pfizer"
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                      "titulo" => "Association between respiratory syncytial virus activity and pneumococcal disease in infants&#58; a time series analysis of US hospitalization data"
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                            0 => "E&#46;J&#46; Nicoli"
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                            3 => "C&#46; Colijn"
                            4 => "P&#46; Waight"
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                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.jinf.2013.02.007"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Infect"
                        "fecha" => "2013"
                        "volumen" => "66"
                        "paginaInicial" => "512"
                        "paginaFinal" => "520"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/23473714"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            6 => array:3 [
              "identificador" => "bib0130"
              "etiqueta" => "7"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Effect of the 2009 influenza A &#40;H1N1&#41; pandemic on invasive pneumococcal pneumonia"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "K&#46;E&#46; Fleming-Dutra"
                            1 => "T&#46; Taylor"
                            2 => "R&#46; Link-Gelles"
                            3 => "S&#46; Garg"
                            4 => "M&#46;A&#46; Jhung"
                            5 => "L&#46; Finelli"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1093/infdis/jit008"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Infect Dis"
                        "fecha" => "2013"
                        "volumen" => "207"
                        "paginaInicial" => "1135"
                        "paginaFinal" => "1143"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/23303809"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            7 => array:3 [
              "identificador" => "bib0135"
              "etiqueta" => "8"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Invasive pneumococcal disease and influenza activity in pediatric population&#46; Impact of PCV13 vaccination in pandemic and non-pandemic influenza periods"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "S&#46; Hern&#225;ndez"
                            1 => "C&#46; Mu&#241;oz-Almagro"
                            2 => "P&#46; Ciruela"
                            3 => "N&#46; Soldevila"
                            4 => "C&#46; Izquierdo"
                            5 => "M&#46;G&#46; Codina"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "J Clin Microbiol"
                        "fecha" => "2019"
                        "volumen" => "57"
                        "numero" => "8&#46;"
                        "paginaInicial" => "e00363"
                        "paginaFinal" => "e419"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            8 => array:3 [
              "identificador" => "bib0140"
              "etiqueta" => "9"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Seasonality of both bacteremic and non-bacteremic pneumonia coincides with viral lower respiratory tract infections in early childhood&#44; in contrast to non-pneumonia invasive pneumococcal disease&#44; in the pre-PCV era"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [
                            0 => "S&#46; Ben-Shimol"
                            1 => "D&#46; Greenberg"
                            2 => "G&#46; Hazan"
                            3 => "Y&#46; Shemer-Avni"
                            4 => "N&#46; Givon-Lavi"
                            5 => "R&#46; Dagan"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1093/cid/civ023"
                      "Revista" => array:6 [
                        "tituloSerie" => "Clin Infect Dis"
                        "fecha" => "2015"
                        "volumen" => "60"
                        "paginaInicial" => "1384"
                        "paginaFinal" => "1387"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/25595749"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            9 => array:3 [
              "identificador" => "bib0145"
              "etiqueta" => "10"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Xarxa bronquiolitis&#46; Informe 2013&#8211;14"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [
                            0 => "L&#46; Espinosa"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Libro" => array:1 [
                        "fecha" => "2020"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            10 => array:3 [
              "identificador" => "bib0150"
              "etiqueta" => "11"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Estudio prospectivo multic&#233;ntrico de la meningitis bacteriana grave pedi&#225;trica"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "J&#46; Casado Flores"
                            1 => "M&#46;A&#46; Garc&#237;a Teresa"
                            2 => "F&#46;J&#46; Cambra"
                            3 => "J&#46; Pilar Orive"
                            4 => "J&#46;L&#46; Teja"
                            5 => "A&#46; Rodr&#237;guez N&#250;&#241;ez"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "An Esp Pediatr"
                        "fecha" => "1997"
                        "volumen" => "47"
                        "paginaInicial" => "466"
                        "paginaFinal" => "472"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/9586285"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            11 => array:3 [
              "identificador" => "bib0155"
              "etiqueta" => "12"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Pneumococcal pneumonia requiring hospitalization in US children in the 13-valent pneumococcal conjugate vaccine era"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "L&#46; Olarte"
                            1 => "W&#46;J&#46; Barson"
                            2 => "R&#46;M&#46; Barson"
                            3 => "J&#46;R&#46; Romero"
                            4 => "J&#46;S&#46; Bradley"
                            5 => "T&#46;Q&#46; Tan"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1093/cid/cix115"
                      "Revista" => array:6 [
                        "tituloSerie" => "Clin Infect Dis"
                        "fecha" => "2017"
                        "volumen" => "64"
                        "paginaInicial" => "1699"
                        "paginaFinal" => "1704"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/28199482"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            12 => array:3 [
              "identificador" => "bib0160"
              "etiqueta" => "13"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Derrame paraneum&#243;nico complicado&#58; an&#225;lisis de 2 cohortes consecutivas tratadas con distinto criterio"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "L&#46; Moral"
                            1 => "C&#46; Loeda"
                            2 => "F&#46; G&#243;mez"
                            3 => "M&#46;A&#46; Pena"
                            4 => "M&#46; Mart&#237;nez"
                            5 => "J&#46;M&#46; Cerd&#225;n"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [
                        "tituloSerie" => "An Pediatr &#40;Barc&#41;"
                        "fecha" => "2016"
                        "volumen" => "84"
                        "paginaInicial" => "46"
                        "paginaFinal" => "53"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            13 => array:3 [
              "identificador" => "bib0165"
              "etiqueta" => "14"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Vaccine failures in patients properly vaccinated with 13-valent pneumococcal conjugate vaccine in Catalonia&#44; a region with low vaccination coverage"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "F&#46; Moraga-Llop"
                            1 => "J&#46;J&#46; Garc&#237;a-Garc&#237;a"
                            2 => "A&#46; D&#237;az-Conradi"
                            3 => "P&#46; Ciruela"
                            4 => "J&#46; Mart&#237;nez-Osorio"
                            5 => "S&#46; Gonz&#225;lez-Peris"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1097/INF.0000000000001041"
                      "Revista" => array:6 [
                        "tituloSerie" => "Pediatr Infect Dis J"
                        "fecha" => "2016"
                        "volumen" => "35"
                        "paginaInicial" => "460"
                        "paginaFinal" => "463"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/26658626"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            14 => array:3 [
              "identificador" => "bib0170"
              "etiqueta" => "15"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Rise of multidrug-resistant Streptococcus pneumoniae clones expressing non-vaccine serotypes among children following introduction of the 10-valent pneumococcal conjugate vaccine in Bulgaria"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "L&#46; Setchanova"
                            1 => "A&#46; Alexandrova"
                            2 => "D&#46; Pencheva"
                            3 => "I&#46; Sirakov"
                            4 => "K&#46; Mihova"
                            5 => "R&#46; Kaneva"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.jgar.2018.05.012"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Glob Antimicrob Resist"
                        "fecha" => "2018"
                        "volumen" => "15"
                        "paginaInicial" => "6"
                        "paginaFinal" => "11"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/29803821"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            15 => array:3 [
              "identificador" => "bib0175"
              "etiqueta" => "16"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Burden of Streptococcus pneumoniae sepsis in children after introduction of pneumococcal conjugate vaccines&#58; a prospective population-based cohort study"
                      "autores" => array:1 [
                        0 => array:3 [
                          "colaboracion" => "Swiss Paediatric Sepsis Study group"
                          "etal" => true
                          "autores" => array:6 [
                            0 => "S&#46;A&#46; Asner"
                            1 => "P&#46;K&#46;A&#46; Agyeman"
                            2 => "E&#46; Gradoux"
                            3 => "K&#46;M&#46; Posfay-Barbe"
                            4 => "U&#46; Heininger"
                            5 => "E&#46; Giannoni"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1093/cid/ciy1139"
                      "Revista" => array:7 [
                        "tituloSerie" => "Clin Infect Dis"
                        "fecha" => "2019"
                        "volumen" => "69"
                        "paginaInicial" => "1574"
                        "paginaFinal" => "1580"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/30601988"
                            "web" => "Medline"
                          ]
                        ]
                        "itemHostRev" => array:3 [
                          "pii" => "S0049017218304931"
                          "estado" => "S300"
                          "issn" => "00490172"
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            16 => array:3 [
              "identificador" => "bib0180"
              "etiqueta" => "17"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Parapneumonic pleural effusions caused by Streptococcus pneumoniae serotype 3 in children immunized with 13-valent conjugated pneumococcal vaccine"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "C&#46; Antachopoulos"
                            1 => "M&#46;N&#46; Tsolia"
                            2 => "G&#46; Tzanakaki"
                            3 => "A&#46; Xirogianni"
                            4 => "O&#46; Dedousi"
                            5 => "G&#46; Markou"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1097/INF.0000000000000041"
                      "Revista" => array:6 [
                        "tituloSerie" => "Pediatr Infect Dis J"
                        "fecha" => "2014"
                        "volumen" => "33"
                        "paginaInicial" => "81"
                        "paginaFinal" => "83"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/24172850"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            17 => array:3 [
              "identificador" => "bib0185"
              "etiqueta" => "18"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Serotype 3 is a common serotype causing invasive pneumococcal disease in children less than 5 years old&#44; as identified by real-time PCR"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "L&#46; Selva"
                            1 => "P&#46; Ciruela"
                            2 => "C&#46; Esteva"
                            3 => "M&#46;F&#46; de Sevilla"
                            4 => "G&#46; Codina"
                            5 => "S&#46; Hernandez"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1007/s10096-011-1468-7"
                      "Revista" => array:6 [
                        "tituloSerie" => "Eur J Clin Microbiol Infect Dis"
                        "fecha" => "2012"
                        "volumen" => "31"
                        "paginaInicial" => "1487"
                        "paginaFinal" => "1495"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/22052607"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
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              "identificador" => "bib0190"
              "etiqueta" => "19"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Early trends for invasive pneumococcal infections in children after the introduction of the 13-valent pneumococcal conjugate vaccine"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "S&#46;L&#46; Kaplan"
                            1 => "W&#46;J&#46; Barson"
                            2 => "P&#46;L&#46; Lin"
                            3 => "J&#46;R&#46; Romero"
                            4 => "J&#46;S&#46; Bradley"
                            5 => "T&#46;Q&#46; Tan"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
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                        "paginaFinal" => "207"
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                    ]
                  ]
                ]
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Journal Information
Vol. 94. Issue 1.
Pages 19-27 (1 January 2021)
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3886
Vol. 94. Issue 1.
Pages 19-27 (1 January 2021)
Original Article
Open Access
Characteristics of patients with invasive pneumococcal disease requiring admission to intensive care units
Características de los pacientes con enfermedad neumocócica invasora que requieren ingreso en la unidad de cuidados intensivos
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3886
Alvaro Díaz-Conradia,
Corresponding author
adiaz@hospitaldenens.com

Corresponding author.
, Juan José García-Garcíab, Sebastià González Perisc, Mariona Fernández de Sevillab, Fernando Moraga Llopc, Paula Sol Venturaa, Angela Domínguezd, On behalf of the Grupo Barcino
a Hospital HM Nens, HM Hospitales, Barcelona, Spain
b Hospital Sant Joan de Déu de Barcelona, Universidad de Barcelona, Barcelona, Spain, Enfermedades Prevenibles y Vacunas, Instituto de Investigación Sant Joan de Déu, Esplugues, Barcelona, CIBER de Epidemiología y Salud Pública (CIBERESP), Madrid, Spain
c Hospital Universitari Vall d’Hebron, Barcelona, Spain
d CIBER de Epidemiología y Salud Pública (CIBERESP), Madrid, Spain, Departamento de Medicina, Universidad de Barcelona, Barcelona, Spain
Members of the Group for the Study of Invasive Pneumococcal Disease in Catalonia (Estudio de la Enfermedad Invasora Neumocócica en Cataluña, Barcino)
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Table 1. Characteristics of patients with invasive pneumococcal disease, compared based on the need for admission in the paediatric intensive care unit.
Abstract
Introduction

Patients with invasive pneumococcal disease (IPD) may require admission into paediatric intensive care units (PICU). The aim of this study is to analyse the epidemiological, clinical, and microbiological characteristics associated with IPD that may require admission to the PICU.

Material and methods

A prospective study was conducted on cases of IPD diagnosed in three Paediatric Hospitals in Barcelona between January 2012 and June 2016. An analysis was made of the associations between the admission to PICU and the epidemiological, clinical, and microbiological variables.

Results

A total of 263 cases with IPD were included, of which 19% (n=50) required admission to PICU. Patients with septic shock (7; 100%), meningitis (16; 84.2%), and those with complicated pneumonia (23; 15.2%) were admitted to the PICU. The most frequent complications were pulmonary (35.2%) and neurological (39.5%). The ratio between admission and non-admission to PICU was 4.7 times higher in subjects with an underlying disease. The serotypes associated with PICU admission were 19A (23% of the total of this serotype), serotype 14 (20%), serotype 3 (17%), and serotype 1 (12.5%).

Conclusions

IPD required PICU admission in cases of septic shock and meningitis, and less so with complicated pneumonia. The percentage of admissions is greater in children with an underlying disease. Admission into the PICU involves a longer stay, complications during the acute phase, as well as sequelae, particularly neurological ones. The serotypes of the patients that were admitted to PICU were predominantly vaccine serotypes.

Keywords:
Streptococcus pneumoniae
Paediatric intensive care
Invasive pneumococcal disease
Resumen
Introducción

La enfermedad neumocócica invasora (ENI) puede requerir ingreso en la unidad de cuidados intensivos pediátricos (UCIP). El objetivo de este trabajo es analizar las características epidemiológicas, clínicas y microbiológicas asociadas a la ENI que predisponen el ingreso en la UCIP.

Material y métodos

Estudio prospectivo de casos diagnosticados con ENI en tres hospitales pediátricos de Barcelona entre enero de 2012 y junio de 2016. Se analizaron las asociaciones entre el ingreso en la UCIP y las variables epidemiológicas, clínicas y microbiológicas.

Resultados

Se incluyeron 263 casos con ENI. El 19% (n=50) requirió ingreso en la UCIP. El 100% (7) de los pacientes con shock séptico, 84,2% (16) con meningitis y 15,2% (23) con neumonía complicada ingresaron en la UCIP. Las complicaciones más frecuentes fueron pulmonares (35,2%) y neurológicas (39,5%). La razón entre ingreso y no ingreso en la UCIP fue 4,17 veces mayor en los sujetos con enfermedad de base. Los serotipos asociados al ingreso en la UCIP fueron el 19A (23% del total de este serotipo), el 14 (20%), el 3 (17%) y el serotipo 1 (12,5%).

Conclusiones

La ENI requiere ingreso en la UCIP en caso de shock séptico y meningitis, no así, de entrada, la neumonía complicada. El porcentaje de ingresos es mayor en los niños con enfermedad de base. El ingreso en la UCIP conlleva una estancia más prolongada, así como complicaciones durante la fase aguda y secuelas, sobre todo, neurológicas. Los serotipos de los pacientes que ingresaron en la UCIP fueron, predominantemente, serotipos vacunales.

Palabras clave:
Streptococcus pneumoniae
Cuidados intensivos pediátricos
Enfermedad neumocócica invasora
Full Text
Introduction

Invasive pneumococcal disease (IPD) continues to cause significant morbidity and mortality in the paediatric population of Spain, even after the introduction in our country of the pneumococcal conjugate vaccine.1 The incidence of IPD in children under 5 years in Spain ranges between 16.8 (2012) and 12.3 (2015) per 100000 inhabitants.1,2

In some cases, it requires admission to the paediatric intensive care unit (PICU) due to the severity of the symptoms. Some forms of IPD, such as sepsis or meningitis, require intensive care from onset, with management based on the continuous monitoring and intensive treatment that these forms require once they are diagnosed. Other forms, such as complicated pneumonia, do not always require admission to the PICU to be cured and could be managed initially in a hospital without paediatric intensive care services.3

The aim of our study was to analyse the epidemiological, microbiological and clinical characteristics of cases of IPD potentially requiring admission to the PICU.

MethodsStudy design

We conducted a prospective study in children aged 2 to 59 months given a diagnosis of IPD between January 1, 2012 and June 30, 2016 managed in 3 children's hospitals in Barcelona, Spain (Hospital Sant Joan de Déu, Hospital Materno-Infantil Vall d’Hebron and Hospital HM Nens) with an estimated cumulative catchment population under 5 years of 116279 inhabitants (30.4% of the total population aged <5 years in Catalonia).2 The first 2 hospitals have a PICU and are the 2 referral PICUs in Catalonia, although there are other PICUs in the region.

We defined IPD as clinical manifestations of infection in addition to isolation of Streptococcus pneumoniae or detection of DNA corresponding to the LytA gene and an additional capsule gene by reverse transcription polymerase chain reaction (RT-PCR) in a sample collected from a normally sterile site.

Demographic, clinical and epidemiological variables

For each case of IPD, we collected data on the following demographic, clinical and epidemiological variables: age, sex, date of birth, date of onset, date of hospital admission, form of IPD (meningitis, septic shock, complicated or uncomplicated pneumonia, occult bacteraemia and other, less frequent forms), complications, admission to PICU and length of stay, presence of medical risk factors (sickle cell anaemia, congenital or acquired asplenia, infection by human immunodeficiency virus, cochlear implant, severe congenital immunodeficiency requiring treatment, chronic heart disease requiring treatment or surgically corrected, chronic respiratory disease including asthma treated with high-dose steroids (methylprednisolone at a dose >1mg/kg/day for longer than 1 month), cerebrospinal fluid fistula, chronic renal failure including nephrotic syndrome requiring dialysis, immunosuppressive therapy or radiotherapy in the past 6 months, solid organ or haematopoietic stem cell transplantation, and insulin-dependent diabetes mellitus), date of discharge and outcome at discharge (discharge without sequelae, discharge with sequelae, death). We considered that pneumonia was complicated in case of lung consolidation with more than one of the following: pleural effusion greater than 10mm, loculated pleural effusion, parapneumonic empyema, necrotising pneumonia or pulmonary abscess. We assessed for the presence of sequelae at 6 months from diagnosis.

Identification, serotyping and classification of S. pneumoniae

Strains isolated from culture were serotyped by means of the Quellung reaction or a dot blot assay in the Pneumococcus Reference Laboratory of the Centro Nacional de Microbiología (National Centre of Microbiology) in Majadahonda (Madrid, Spain). In patients in which the pneumococcal strain could not be isolated from culture, serotyping was performed by means of RT-PCR, which allows detection of 43 different serotypes/serogroups with the multilocus sequence typing (MLST) method, which is recognised at the international level.

Since PCR does not differentiate between serotypes 6A and 6C, 7F and 7A, 9V, 9A and 9N and 19F, 19B and 19C, we only considered serotypes 6A, 7F, 9V and 19F as vaccine serotypes once their identification was confirmed by the Pneumococcus Reference Laboratory in Majadahonda.2

Genotyping from samples was performed at the Molecular Biology Laboratory of the Hospital Sant Joan de Déu with the MLST method. We identified allelic profiles and sequence types with the software available at http://pubmlst.org/spneumoniae/. We analysed sequence types and assigned specific clonal complexes using the eBURST algorithm.

Criteria for admission to the PICU

The children admitted to the PICU met all or some of the following criteria: IPD with severe haemodynamic instability that did not improve with administration of 1 or 2 boluses of fluids; diagnosis of meningitis; development of acute respiratory distress syndrome defined as a ratio of arterial oxygen partial pressure (PaO2) to fractional inspired oxygen (FiO2) of 200 to 250; need for invasive or non-invasive mechanical ventilation; signs of acute renal failure (2-fold or greater increase in serum creatinine relative to baseline over a 12–24h interval); disseminated intravascular coagulation; Glasgow coma scale score of less than 8.3

Vaccination against pneumococcus

We obtained the vaccination status of each patient with IPD from the official vaccination history card, the records of the public or private primary care centre that managed the child routinely or the patient health records. We defined correct vaccination as having received every dose of pneumococcal 13-valent conjugate vaccine (PCV13) scheduled up to the patient's age as established by the summary of product characteristics.4

Statistical analysis

We assessed the association between categorical variables with the χ2 test or the Fisher exact test, and the association between continuous variables with the Student t test. To estimate the strength of the association between the variables under study and admission to the PICU, we calculated odds ratios (ORs) with the corresponding 95% confidence intervals (CIs). We defined statistical significance as a P-value of .05. All tests were two-tailed.

Ethical considerations

The study was approved by the ethics committees of the 3 participating hospitals. The guardians of the patient signed an informed consent document stating that they understood the study, accepted to participate and had the right to withdraw at any time.

Results

The study included 263 patients with IPD (155 male and 108 female), with a mean age of 45 months (standard deviation [SD], 37.1), out of who 50 (19%) required admission to the PICU at some point in the course of disease (Group 1). The remaining 213 patients did not require admission to the PICU (Group 2). The incidence of IPD peaked in February (n=54; 20.5%) and March (n=44; 16.7%), while admission to the PICU peaked in March (n=10; 20%) and December (n=7; 14%) (Fig. 1A).

Figure 1.

Characteristics of patients based on whether or not they required admission to the paediatric intensive care unit (PICU). (A) Month of the year invasive pneumococcal disease was diagnosed. (B) Clinical presentation. (C) Complications. (D) Sequelae.

(0.32MB).

The length of stay was significantly longer in patients that required admission to the PICU (19.8±12.5 days) compared to those that did not (9.6±5.8 days) (P<.001). We found that 46.7% of patients with underlying disease required admission to the PICU compared to 17.3 of patients that were previously healthy. The ratio of the number of patients admitted to the PICU to the number not admitted was 4.17 times greater in patients with underlying disease compared to previously healthy patients, and this association was statistically significant (OR, 4.17; 95% CI, 1.44–12.12).

The forms of IPD found in the total sample were (n; %): complicated pneumonia (152; 57.4%), uncomplicated pneumonia (43; 16.3%), occult bacteraemia (25; 9.5%), meningitis (19; 7.2%), septic shock (7; 2.7%), mastoiditis (7; 2.7%), osteoarticular infection (7; 2.7%), orbital cellulitis (2; 0.8%), peritonitis (1) and pancreatitis (1). In group 1, the patients admitted to the PICU included 100% of patients with septic shock (OR, 5.95; 95% CI, 4.53–7.82), 84.2% of patients with meningitis (OR, 32.94; 95% CI, 9.11–119.10) and 15.2% of patients with complicated pneumonia (OR, 0.57; 95% CI, 0.30–1.50), although in the latter case the association with PICU admission was not statistically significant. Group 2, composed of the patients that did not require PICU admission, included 95% of the patients with uncomplicated (OR, 0.18; 95% CI, 0.04–0.75) (Table 1 and Fig. 1B).

Table 1.

Characteristics of patients with invasive pneumococcal disease, compared based on the need for admission in the paediatric intensive care unit.

  PICU (n=50) n (%)  No PICU (n=213) n (%)  P (Student tRaw OR (95% CI)  Adjusted OR (95% CI) 
Age (months)  36.9±36.1 (26.7–47.2)  47.6±37.4 (42.6–52.7)  .067  –  – 
Sex
Male  28 (18.1%)  127 (81.9%)  .220.639  0.86 (0.46–1.6)  0.37 (0.12–1.19) 
Female  22 (20.4%)  86 (79.6%)       
Hospital length of stay in days  9.6±5.8 (8.8–10.4)  19.8±12.5 (16.2–23.4)  <.001  –  – 
Underlying disease
Yes  7 (46.7%)  8 (53.3%)  .011  4.17 (1.44–12.12)  4.97 (0.61–40.64) 
No  43 (17.3%)  205 (82.7%)       
Clinical presentation
Septic shock
Yes  7 (100%)  0 (0%)  <.001  5.95 (4.53–7.82)   
No  43 (16.8%)  213 (83.2%)       
Meningitis
Yes  16 (84.2%)  3 (15.8%)  <.001  32.94 (9.11–119.10)  15.27 (2.39–97.67) 
No  34 (13.9%)  210 (86.1%)       
Complicated pneumonia
Yes  23 (15.2%)  128 (84.8%)  .07  0.57 (0.304–1.50)   
No  27 (24.1%)  85 (75.9%)       
Uncomplicated pneumonia
Yes  2 (4.7%)  41 (95.3%)  .009  0.18 (0.04–0.75)  0.21 (0.03–1.41) 
No  48 (21.8%)  172 (78.2%)       
Bacteraemia
Yes  1 (4.0%)  24 (96.0%)  .081  0.16 (0.02–1.21)  0.11 (0.01–1.31) 
No  49 (20.6%)  189 (79.4%)       
Other presenting symptoms
Yes  1 (5.6%)  17 (94.4%)  .232  0.24 (0.03–1.81)   
No  49 (20%)  196 (80%)       
Acute complications
None  12 (12.9%)  81 (87.1%)      Ref. 
Neurologic  12 (85.7%)  2 (14.3%)  <.001  33.3 (7.17–154.8)  7.53 (0.83–68.23) 
Respiratory  24 (15.8%)  128 (84.2%)  .536  0.613 (0.33–1.14)   
Other  2 (50%)  2 (50%)  .18  4.4 (0.6–31.9)   
Sequelae
None  33 (14.4%)  194 (85.5%)       
Neurologic  7 (87.5%)  1 (12.5%)  <.001  37.1 (4.44–309.9)   
Respiratory  5 (22.7%)  17 (77.3%)  .54  1.4 (0.48–3.93)   
Other  2 (66.7%)  1 (33%)  .028  9.4 (0.84–106.2)   
PCV13 vaccination
Complete  5 (11.1%)  40 (88.9%)  (.14)  0.48 (0.18–1.29)   
Incomplete or unvaccinated  45 (20.6%)  172 (79.4%)       

CI, confidence interval; OR, odds ratio; PICU, paediatric intensive care unit; PCV13, pneumococcal conjugate 13-valent vaccine.

* We applied the continuity correction to the χ2 test when at least 1 expected frequency <5.

Quantitative data expressed as mean±standard deviation (95% CI).

In both groups 1 and 2, 64.4% of patients with IPD experienced some form of complication; 57.8% were respiratory complications and 5.3% neurologic complications. Of the patients with neurologic complications during the acute phase, 85.7% required admission to the PICU (OR, 33.3; 95% CI, 7.17–154.8), as did 15.8% of the patients with respiratory complications (OR, 0.613; 95% CI, 0.33–1.14) (Fig. 1C).

Of the 260 patients with IPD for who follow-up data were available, 85.5% were free of sequelae at 6 months. Two patients died and 1 did not attend the follow-up visit. Out of the patients with immediate sequelae, 22 (8.5%) had respiratory sequelae and 8 (3.1%) neurologic sequelae (including 2 patients with hearing loss); 1 patient had high blood pressure, 1 required a radical mastoidectomy and 1 had cavernous sinus thrombosis. In group 1, 14.3% of patients developed neurologic sequelae (OR, 37.1; 95% CI, 4.4–309-9), followed in frequency by respiratory sequelae in 10.2% (OR, 1.4; 95% CI, 0.48–3.93) (Fig. 1D).

Of all patients with IPD, 84.8% (223/263) had not received antibiotherapy at the outpatient level before admission, and 20.6% of these subset of patients (46/223) belonged to group 1 (OR, 0.43; 95% CI, 0.145–1.26; P=.115).

We found that 50.4% (132/263) of patients, without differences between groups, had received at least 1 dose of pneumococcal conjugate vaccine. Only 28.1% were correctly vaccinated for their age (8.7% with PCV7; 2.3% with PVC10 and17.1% with PCV13). We did not find an association between the need for admission to the PICU (group 1) and complete PCV13 vaccination status (OR, 0.48; 95% CI, 0.18–1.3) (P=.135).

The serotypes identified most frequently in both groups were serotype 3 (53 [20.2%], of who 17% required PICU admission), serotype 1 (48 [18.3%], of who 12.5% required PICU admission), other nonvaccine serotypes (33 [12.5%], of who 21% required PICU admission), serotype 19A (17; 6.5%, of who 23% required PICU admission) and serotype 14 (15 [5.7%], of who 20% required PICU admission). The serotypes identified most frequently in patients of group 1 were (n, %): serotype 3 (9; 18%), other nonvaccine serotypes (7; 14%), serotype 1 (6; 12%) and serotype 19A (4; 8%). The most frequent nonvaccine serotypes in group 1 were serotypes 10A (2; 4%) and 11 (2; 4%) (Fig. 2). There was only 1 case of vaccine failure in this group, corresponding to a patient with infection by serotype 3. When it came to genotyping, the only salient finding in group 1 was detection of sequence type 306, corresponding to serotype 1, in 4/6 cases; the rest of sequence types and clonal complexes varied and were not associated significantly with PICU admission.

Figure 2.

Frequency distribution of serotypes in patients that required admission to the paediatric intensive care unit (PICU) and patients that did not.

(0.18MB).
Discussion

Admission to the PICU is a possible development in the context of IPD, so the exploration of the epidemiological, microbiological and clinical factors may be associated with an increased likelihood of admission to the PICU is a relevant pursuit. In our study, we identified factors associated with an increased probability of admission to the PICU, such as age less than 1 year at the time of diagnosis, the presence of underlying disease that increases the risk of IPD, specific presentations of IPD such as septic shock or meningitis and the months of the year corresponding to seasonal viral disease outbreaks.

The two seasonal peaks in the incidence of IPD and the peak in the proportion of patients with IPD requiring PICU admission coincided with the annual outbreaks of bronchiolitis due to respiratory syncytial virus (RSV) and influenza, as described in previous studies.5–9 However, while the incidence of IPD peaked in February and March (and the influenza outbreak occurred between week 50 of 2013 and week 12 of 201410), the months corresponding to the highest proportion of IPD cases requiring PICU admission were November and December (overlapping with the RSV season that happens between week 40 of one year and week 4 of the following year10). This could be explained by different factors, such as the lower age of patients with bronchiolitis, the virulence of the virus involved in the RSV or flu season, and the previous health of the patient.6,7

Outpatient management with antibiotherapy previous to hospital admission does not have a protective effect against admission to the PICU, as we found in our series and in reviewing the work of other authors.11

The total length of stay was greater in patients admitted to the PICU, which was consistent with the findings of previous studies.12 When it came to the forms of IPD that required admission to the PICU, we found that the only feature present in 100% of the patients admitted to the PICU was haemodynamic instability. Although a diagnosis of meningitis was in itself a criterion for admission to the PICU, it was not always made at the outset and patients with a discharge diagnosis of meningitis that were not admitted to the PICU had favourable outcomes. This was because 39.5% of the patients with meningitis admitted to the PICU had complications during the acute phase, as was observed in other studies, such as the one published by Casado et al.11 Most children with IPD admitted to the PICU recovered and were free of sequelae. The most frequent sequelae were neurologic, followed by respiratory sequelae. Only 15.2% of patients with complicated pneumonia with pleural effusion or empyema required admission to the PICU, which demonstrates that these patients may be managed in a hospital without an intensive care unit under close monitoring.11,13

Although the most prevalent serotypes (especially 19A) are covered by the PCV13, 11.8% of the patients with complete PCV13 vaccination were admitted to the PICU compared to 18.5% of patients without complete vaccination (P=.23), a difference that was not statistically significant. Thus, in our study, complete vaccination with PCV13 did not exhibit a protective effect as concerned admission to the PICU. The only case of vaccine failure in a patient that required intensive care involved serotype 3, against which the PCV13 proved to be less effective compared to other serotypes, as found in previous studies.14–16 Asner et al.16 reported vaccine failure in 26% of patients that required admission to the PICU, with many of these cases involving serotype 3. We ought to mention 2 serotypes that are not included in the PCV13, 10A and 11A, which, while infrequent among our patients, are associated with a high proportion of PICU admission. In a prospective study conducted in Switzerland that included 117 patients with IPD, patients with meningitis, especially those with infection by non-vaccine serotypes, were most likely to require admission to the PICU.16

When it came to the serotypes involved in IPD, in our study serotype 3 was the one corresponding to the highest proportion of affected patients requiring admission to the PICU, which may be attributable to the characteristics of this serotype, which has capsule proteins resulting in greater virulence,17,18 and the lower efficacy of the PCV13 against this serotype, described in the previous literature.14,17,18 This was also the serotype most frequently associated with development of IPD and with vaccine failure in our study.

These results evince the need of ongoing surveillance of pneumococcal serotypes involved in IPD and their genotypes to have updated information on the aetiological agents of IPD in the local population at all times.19

There are limitations to our study. First of all, the sample only included 30.4% of the population under 5 years in Catalonia, as we only studied IPD in 3 of the hospitals in the region. Secondly, only 2 of the 3 participating hospitals had a PICU, and while these 2 units are the referral PICUs in Catalonia, there are other hospitals that manage patients with IPD. Third of all, there may have been biases associated with the documentation of clinical data in the health records, and some pneumococcal strains were not analysed, meaning the resulting information was not available for 100% of the cases. Lastly, data collection in the last year included in the study period ended in June, which means that the study did not include data corresponding to the bronchiolitis season of that year.

Conclusions

In our series, the presence of septic shock and/or neurologic involvement in the context of IPD was associated with admission to the PICU, and the proportion of patients admitted to the PICU was higher in the group of patients with underlying disease. The frequency of PICU admission increased during the annual bronchiolitis season. Admission to the PICU was associated with a longer length of stay in hospital, a higher prevalence of complications in the acute phase and a higher prevalence of sequelae, mainly neurologic. The most frequent serotypes involved in the group of patients admitted to the PICU were vaccine serotypes (19A, 14, 3 and 1). Admission to the PICU in the context of IPD is necessary in patients that develop septic shock or neurologic complications. In case of complicated pneumonia, it is possible to manage the patient in the paediatric ward under close monitoring.

Funding

National R&D& programme, Instituto de Salud Carlos III-Vice Directorate General of Evaluation and Promotion of Research in Health Care. Grant no. P111/02081, PI 11/2345; European Regional Development Fund (ERDF) and Agencia de Gestión de Ayudas Universitarias y de Investigación (AGAUR). Grant no. 2017 SGR 1342.

Declaration of Competing Interest

No conflicts of interest.

Appendix A
Members of the Group for the Study of Invasive Pneumococcal Disease in Catalonia (Estudio de la Enfermedad Invasora Neumocócica en Cataluña, Barcino)

Juan José García García, Angela Domínguez, Fernando Moraga Llop, Alvaro Díaz Conradi, Mariona Fernández de Sevilla, Sebastià González Peris, Pilar Ciruela, Magda Campins, Carmen Muñoz-Almagro, Cristina Esteva, Conchita Izquierdo, Sonia Uriona, Johanna Martínez Osorio, Anna Solé Ribalta, Gemma Codina, Nuria Soldevila y Lluís Salleras Sanmartí.

References
[1]
P. Ciruela, C. Izquierdo, S. Broner, S. Hernandez, C. Muñoz-Almagro, R. Pallares, et al.
Epidemiología de la enfermedad invasiva neumocócica en Cataluña. Reporte 2012-2016.
Agencia de Salut Publica de Catalunya, (2018),
[2]
A. Domínguez, P. Ciruela, S. Hernández, J.J. García-García, N. Soldevila, C. Izquierdo, et al.
Effectiveness of the 13-valent pneumococcal conjugate vaccine in preventing invasive pneumococcal disease in children aged 7-59 months. A matched case-control study.
PLOS ONE, 12 (2017), pp. e0183191
[3]
K.L. O’Brien, L.J. Wolfson, J.P. Watt, E. Henkle, M. Deloria-Knoll, N. McCall, et al.
Burden of disease caused by Streptococcus pneumoniae in children younger than 5 years: global estimates.
[4]
Ficha técnica o resumen de las características de la vacuna antineumocócica polisacárida conjugada (13-valente, adsorbida) Pfizer.
(2010),
[5]
D.M. Weinberger, K.P. Klugman, C.A. Steiner, L. Simonsen, C. Viboud.
Association between respiratory syncytial virus activity and pneumococcal disease in infants: a time series analysis of US hospitalization data.
PLoS Med, 12 (2015), pp. e1001776
[6]
E.J. Nicoli, C.L. Trotter, K.M. Turner, C. Colijn, P. Waight, E. Miller.
Influenza and RSV make a modest contribution to invasive pneumococcal disease incidence in the UK.
J Infect, 66 (2013), pp. 512-520
[7]
K.E. Fleming-Dutra, T. Taylor, R. Link-Gelles, S. Garg, M.A. Jhung, L. Finelli, et al.
Effect of the 2009 influenza A (H1N1) pandemic on invasive pneumococcal pneumonia.
J Infect Dis, 207 (2013), pp. 1135-1143
[8]
S. Hernández, C. Muñoz-Almagro, P. Ciruela, N. Soldevila, C. Izquierdo, M.G. Codina, et al.
Invasive pneumococcal disease and influenza activity in pediatric population. Impact of PCV13 vaccination in pandemic and non-pandemic influenza periods.
J Clin Microbiol, 57 (2019), pp. e00363-e419
[9]
S. Ben-Shimol, D. Greenberg, G. Hazan, Y. Shemer-Avni, N. Givon-Lavi, R. Dagan.
Seasonality of both bacteremic and non-bacteremic pneumonia coincides with viral lower respiratory tract infections in early childhood, in contrast to non-pneumonia invasive pneumococcal disease, in the pre-PCV era.
Clin Infect Dis, 60 (2015), pp. 1384-1387
[10]
L. Espinosa.
Xarxa bronquiolitis. Informe 2013–14.
(2020),
[11]
J. Casado Flores, M.A. García Teresa, F.J. Cambra, J. Pilar Orive, J.L. Teja, A. Rodríguez Núñez, et al.
Estudio prospectivo multicéntrico de la meningitis bacteriana grave pediátrica.
An Esp Pediatr, 47 (1997), pp. 466-472
[12]
L. Olarte, W.J. Barson, R.M. Barson, J.R. Romero, J.S. Bradley, T.Q. Tan, et al.
Pneumococcal pneumonia requiring hospitalization in US children in the 13-valent pneumococcal conjugate vaccine era.
Clin Infect Dis, 64 (2017), pp. 1699-1704
[13]
L. Moral, C. Loeda, F. Gómez, M.A. Pena, M. Martínez, J.M. Cerdán, et al.
Derrame paraneumónico complicado: análisis de 2 cohortes consecutivas tratadas con distinto criterio.
An Pediatr (Barc), 84 (2016), pp. 46-53
[14]
F. Moraga-Llop, J.J. García-García, A. Díaz-Conradi, P. Ciruela, J. Martínez-Osorio, S. González-Peris, et al.
Vaccine failures in patients properly vaccinated with 13-valent pneumococcal conjugate vaccine in Catalonia, a region with low vaccination coverage.
Pediatr Infect Dis J, 35 (2016), pp. 460-463
[15]
L. Setchanova, A. Alexandrova, D. Pencheva, I. Sirakov, K. Mihova, R. Kaneva, et al.
Rise of multidrug-resistant Streptococcus pneumoniae clones expressing non-vaccine serotypes among children following introduction of the 10-valent pneumococcal conjugate vaccine in Bulgaria.
J Glob Antimicrob Resist, 15 (2018), pp. 6-11
[16]
S.A. Asner, P.K.A. Agyeman, E. Gradoux, K.M. Posfay-Barbe, U. Heininger, E. Giannoni, Swiss Paediatric Sepsis Study group, et al.
Burden of Streptococcus pneumoniae sepsis in children after introduction of pneumococcal conjugate vaccines: a prospective population-based cohort study.
Clin Infect Dis, 69 (2019), pp. 1574-1580
[17]
C. Antachopoulos, M.N. Tsolia, G. Tzanakaki, A. Xirogianni, O. Dedousi, G. Markou, et al.
Parapneumonic pleural effusions caused by Streptococcus pneumoniae serotype 3 in children immunized with 13-valent conjugated pneumococcal vaccine.
Pediatr Infect Dis J, 33 (2014), pp. 81-83
[18]
L. Selva, P. Ciruela, C. Esteva, M.F. de Sevilla, G. Codina, S. Hernandez, et al.
Serotype 3 is a common serotype causing invasive pneumococcal disease in children less than 5 years old, as identified by real-time PCR.
Eur J Clin Microbiol Infect Dis, 31 (2012), pp. 1487-1495
[19]
S.L. Kaplan, W.J. Barson, P.L. Lin, J.R. Romero, J.S. Bradley, T.Q. Tan, et al.
Early trends for invasive pneumococcal infections in children after the introduction of the 13-valent pneumococcal conjugate vaccine.
Pediatr Infect Dis J, 32 (2013), pp. 203-207

Please cite this article as: Díaz-Conradi A, García-García JJ, González Peris S, Fernández de Sevilla M, Moraga Llop F, Ventura PS, et al. Características de los pacientes con enfermedad neumocócica invasora que requieren ingreso en la unidad de cuidados intensivos. An Pediatr (Barc). 2021;94:19–27.

Appendix A lists the members of the Group for the Study of Invasive Pneumococcal Disease in Catalonia (Barcino Group).

Previous presentation: This study was presented as an oral communication at the Annual Congress of the Asociación Española de Pediatría, June 6–8, 2019, Burgos, Spain.

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