Recommendations for vaccination against pneumococcus in kidney patients in Spain
Recomendaciones de vacunación frente a neumococo en enfermos renales en España
José Portolés-Péreza, María Marqués-Vidasb, María Marques-Vidasc, Juan J. Picazod, Fernando González-Romod, Amós García-Rojase, Emilio Pérez-Trallerof, Pedro Gil-Gregoriog, Rafael de la Cámarah, M. Luisa Moratói, Alejandro Rodríguezj, José Barberánk, Vicente Domínguez-Hernándezl, Manuel Linares-Rufom, Isabel Jimeno-Sanzn, Francisco Sanz-Herreroo, Javier Espinosa-Arranzp, Valle García-Sánchezq, María Galindo-Izquierdor, Alberto Martínez-Castelaos
a Sociedad Española de Nefrología. Servicio de Nefrología, Hospital Universitario Puerta de Hierro/REDInREN. ISCiii, Madrid,
b Servicio de Nefrología, Hospital Universitario Puerta de Hierro. REDInREN, Madrid, Spain,
c Servicio de Nefrología, Hospital Universitario Puerta de Hierro. REDInREN, Madrid,
d Sociedad Española de Quimioterapia, Infección y Vacunas,
e Asociación Española de Vacunología,
f Sociedad Española de Enfermedades Infecciosas y Microbiología,
g Sociedad Española de Geriatría y Gerontología,
h Sociedad Española de Hematología y Hemoterapia,
i Sociedad Española de Medicina Familiar y Comunitaria,
j Sociedad Española de Medicina Intensiva,
k Sociedad Española de Medicina Interna,
l Sociedad Española de Medicina Preventiva,
m Sociedad Española de Médicos de Atención Primaria,
n Sociedad Española de Médicos Generales y de Familia,
o Sociedad Española de Neumología,
p Sociedad Española de Oncología Médica,
q Sociedad Española de Patología Digestiva,
r Sociedad Española de Reumatología,
s Sociedad Española de Nefrología,
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Renal replacement therapies such as haemofiltration, high-flux HD and haemodiafiltration (HDF) combine diffusion and convection with the objective of increasing clearance of uraemic toxins. Postdilutional online HDF (OL-HDF) is the most used convective therapy because it allows large replacement volumes to be obtained using the dialysate, resulting in maximum clearance of uraemic toxins, as well as good haemodynamic tolerance, thus reducing the complications associated with conventional therapy<span class="elsevierStyleSup">2-4</span>. Since convection is the transport that is predominant in the glomeruli, it is considered to be a more “physiological”, safe and versatile technique because it allows large quantities of replacement fluid to be produced in situ<span class="elsevierStyleSup">5</span>.</p><p class="elsevierStylePara">The addition of the replacement volume and the loss of intradialysis weight (ultrafiltration) constitute the total convective volume<span class="elsevierStyleSup">6</span>. Total convective volume has been directly related to clearance of uraemic molecules, especially those of a medium and large size<span class="elsevierStyleSup">6-8</span>.</p><p class="elsevierStylePara">Several studies suggest a link between convective volume and overall survival. Consequently, retrospective studies such as the European patient subgroup of the Dialysis Outcomes and Practice Pattern Study and randomised studies such as the Turkish OL-HDF and CONTRAST studies have demonstrated the decrease in mortality with replacement volumes of 15, 17.4 and 20, respectively, in post-hoc analysis. The recent ESHOL study demonstrated higher survival in patients who received >23 l of total convective volume<span class="elsevierStyleSup">12</span>.</p><p class="elsevierStylePara">The main limitation to achieving a high convective volume lies in blood flow (Qb) and haemoconcentration. In this regard, the new generation of dialysis machines has improved the software in terms of increasing the total convective volume, optimising infusion flows (Qi) in relation to intradialysis changes<span class="elsevierStyleSup">13</span>. The ultracontrol system in the Gambro machines or the Fresenius 5008 CorDiax automated replacement system are technological advances that attempt to maximise the convective volume administered automatically.</p><p class="elsevierStylePara">Until present, use of the “automated manual” regimen was recommended, in which the values of haematocrit and total protein were modified manually on the monitor in order to optimise the Qi with the lowest number of alarms<span class="elsevierStyleSup">14</span>.</p><p class="elsevierStylePara">The study’s objective was to evaluate the recent version of the 5008 monitor software (CorDiax) compared to that of the previous version on the impact on total convective volume.</p><p class="elsevierStylePara"><span class="elsevierStyleBold"> </span></p><p class="elsevierStylePara"><span class="elsevierStyleBold">PATIENTS AND METHOD</span></p><p class="elsevierStylePara"><span class="elsevierStyleBold"> </span></p><p class="elsevierStylePara">The study was carried out in a hospital in stable HD patients. We included 63 patients, 44 males and 19 females, with a mean age of 65.2 ± 15 years (interval of 26-88 years) who had been on a HD programme for an average of 46.6 ± 52.6 months. The chronic renal failure aetiology was as follows: chronic glomerulonephritis in 12 patients (19%), diabetic nephropathy in 11 (17.5%), polycystic kidney disease in 9 (14.3%), vascular in 6 (9.5%), renal tumour in 4 (6.3%), a urological cause in 2 (3.2%), a systemic cause in 1 (1.6%), tubulointerstitial nephritis in 1 (1.6%) and an unknown cause in 17 (27%). Most patients received dialysis via an arteriovenous fistula (81%) and the remainder, using a catheter (16%) or a polytetrafluoroethylene prothesis.</p><p class="elsevierStylePara">In the first stage, each patient was assessed over three sessions with a 5008 monitor before the change of software was implemented. In the second stage, we recorded three other OL-HDF sessions with the new update.</p><p class="elsevierStylePara">During the week in which the 5008 monitor was used, a Qi was administered using the automated manual regimen, adjusting the haematocrit and total protein to achieve and maintain the Qi prescribed, which was approximately 25% of the Qb. During the second stage of the study, with the new version of the monitor, we used the automated infusion system, in which it was not necessary to introduce any value.</p><p class="elsevierStylePara">We considered the demographic characteristics of each patient: age, sex, time on dialysis, body surface area and body mass index. The dialysis parameters recorded in each session were: time scheduled, real time, dialyser, type of vascular access, blood flow, dialysate flow (Qd), heparin dose, Kt measured automatically by ionic dialysance, recirculation rate, arterial blood pressure, venous blood pressure, transmembrane pressure, initial and final haemoglobin, ultrafiltration, minimum plasma volume, processed blood volume and total convective volume.</p><p class="elsevierStylePara">In the laboratory, we determined haemoglobin, haematocrit and albumin at each stage.</p><p class="elsevierStylePara"><span class="elsevierStyleBold"> </span></p><p class="elsevierStylePara"><span class="elsevierStyleBold">Statistical analysis</span></p><p class="elsevierStylePara"><span class="elsevierStyleBold"> </span></p><p class="elsevierStylePara">Statistical analysis was carried out using the SPSS statistical software version 20.0 and the results were expressed as an arithmetic mean ± standard deviation. To analyse the statistical significance of quantitative parameters, we used Student’s t-test for paired data and the ANOVA test for repeated data. Values of <span class="elsevierStyleItalic">p</span>< 0.05 were considered to be statistically significant.</p><p class="elsevierStylePara"><span class="elsevierStyleBold"> </span></p><p class="elsevierStylePara"><span class="elsevierStyleBold">RESULTS</span></p><p class="elsevierStylePara"><span class="elsevierStyleBold"> </span></p><p class="elsevierStylePara">All dialysis sessions were carried out without notable clinical incidents and with a small number of monitor alarms. The dialysers used were: 1.4 m<span class="elsevierStyleSup">2</span> helixone in 76%, 1.8 m<span class="elsevierStyleSup">2</span> helixone in 19% and 2.1 m<span class="elsevierStyleSup">2</span> polyamide in 5%. Each patient had the same dialyser in both study periods. The anticoagulation used was heparin sodium in 6.4%, low-molecular-weight heparin (tinzaparin or nadroparin) in 79% and the remaining 14.3% sessions were carried out without heparin.</p><p class="elsevierStylePara">The dialysis time prescribed was 288.6 ± 17 min, the Qb was 400 ± 34 mL/min (interval between 300 and 450 mL/min) and the Qd 500 mL/min; we should bear in mind that this flow is that which is going to be processed for diffusion and the Qi is additional.</p><p class="elsevierStylePara">There were no statistically significant differences in the laboratory parameters, the real dialysis time, the Qb or other dialysis parameters (Table 1). The only exception was the ultrafiltration volume: 2.25 l ± 0.92 with the 5008 monitor versus 2.06 l ± 0.85 with the CorDiax monitor (<span class="elsevierStyleItalic">p </span>= 0.005). Arterial pressure, venous pressure and transmembrane pressure were similar in both study periods, as well as the recirculation rate, the processed blood volume and the dialysis dose measured by ionic dialysance and expressed as Kt (Table 1).</p><p class="elsevierStylePara">The replacement volume was significantly higher with the 5008 CorDiax monitor: 31.2 ± 3.4 l, versus the 5008 monitor: 27.2 L ± 2.8, <span class="elsevierStyleItalic">p</span>< 0.001. These differences are maintained when we separate the sessions into the three days of the week (Figure 1). Table 2 also displays the absolute total convective volume, as well as volume related to dry weight, body surface area and body mass index and lastly the effective convective volume percentage of the total processed blood, with the differences being significant in all cases. Patients with a catheter received a replacement volume below that of those with fistulas; however, upon changing to the 5008 CorDiax monitor, there was a significant increase in the replacement volume in patients with fistulas and those with tunnelled venous catheters (Figure 2).</p><p class="elsevierStylePara">The replacement volume increase was maintained regardless of the dialyser used, 27.43 ± 2.5 versus 31.38 ± 3.2 l with 1.4 m<span class="elsevierStyleSup">2 </span>helixone, 27.47 ±  2.6 versus 31.71 ± 3.0 with 1.8 m<span class="elsevierStyleSup">2 </span>helixone, and 26.08 ± 4.9 versus 31.57 ± 5.8 with 2.1 m<span class="elsevierStyleSup">2</span> polyamide (<span class="elsevierStyleItalic">p</span>< 0.001 in all cases).</p><p class="elsevierStylePara"><span class="elsevierStyleBold"> </span></p><p class="elsevierStylePara"><span class="elsevierStyleBold">DISCUSSION</span></p><p class="elsevierStylePara"><span class="elsevierStyleBold"> </span></p><p class="elsevierStylePara">This study shows that it is possible to increase the total convective volume with postdilution OL-HDF with the only change being the new dialysis machine software, without modifying any of the other dialysis parameters.</p><p class="elsevierStylePara">OL-HDF is a safe technique that improves intradialysis haemodynamic tolerance<span class="elsevierStyleSup">15</span>. Currently, the ESHOL study has contributed scientific evidence that patients who receive postdilution OL-HDF have increased survival compared those on HD<span class="elsevierStyleSup">12</span>. A subsequent meta-analysis that includes the three main randomised multi-centre studies<span class="elsevierStyleSup">10-12</span> has confirmed that OL-HDF reduces overall mortality by 16%<span class="elsevierStyleSup">16</span>. These data lead us to predict a progressive increase in this technique, and it will probably become the standard treatment in the near future.</p><p class="elsevierStylePara">However, there are still issues to be resolved with regard to HDF techniques. The first is a conceptual redesign. According to the Eudial group, HDF is a blood clearance treatment that combines diffusive and convective transport using a high-flux dialyser with the following characteristics: an ultrafiltration coefficient greater than 20 mL/mmHg/h/m<span class="elsevierStyleSup">2</span> and a screening coefficient for ß2-microglobulin greater than 0.6. It is considered that the minimum effective convective transport percentage must be greater than 20% of the total blood processed<span class="elsevierStyleSup">6</span>.</p><p class="elsevierStylePara">A second issue to discuss is what the adequate convective volume should be per session. In a post-hoc analysis that assessed mortality in relation to the convective volume received, in the three randomised clinical trials, there was superiority in receiving a high convective volume. In the Turkish study, when we analysed the patients by the median reinfusion volume, 17.4 l, we found a 46% reduction in mortality<span class="elsevierStyleSup">10</span>. In the CONTRAST and ESHOL studies, the analysis was carried out separating patients into terciles and they found a reduction in mortality when they received a total convective volume greater than 22 and 23 L, respectively. Logically, since it was a secondary analysis, there was a selection bias, since the patients who achieved a higher convective volume could be younger, with better vascular access and lower comorbidity<span class="elsevierStyleSup">11,12</span>.</p><p class="elsevierStylePara">The main limiting factors in achieving high convective volumes were Qb, time and haemoconcentration in the dialyser. In recent years, there has been technological development with the aim of achieving an increase in convective volume. New dialysers were developed with an increased pore size and some were developed with an increase in the diameter of the capillary fibres specifically designed to increase the convective volume. The other advancement corresponded to the development of new dialysis monitors that allow an automated Qi in order to maximise the convective volume. The 5008 CorDiax monitor software update is based on the dynamic analysis of the pressure pulse signals that are generated when blood passes through the filter, and using an internal algorithm, the machine automatically regulates the Qi to the highest possible volume at each moment. This system, known as <span class="elsevierStyleItalic">AutoSub plus, </span>uses the already existing signals of pressure pulses created continuously by rotation of the blood pump, venous blood pressure and transmembrane pressure. The frequency and amplitude of these signals are measured by the venous pressure sensor, allowing analysis of stress in the dialyser capillary dynamically, and optimising continuously the Qi administered.</p><p class="elsevierStylePara">As for haemoconcentration, there is a difference between haematocrit and albumin levels. In an analysis of the factors that determine the convective volume carried out in the CONTRAST<span class="elsevierStyleSup">17 </span>study, there was an inverse relationship between haematocrit levels and the convective volume; however, they found a direct correlation with pre-dialysis albumin values (there was an increase of 1 l of convective volume per session for each 10 g/l of albumin). It seems that, a higher albumin value increases oncotic pressure and facilitates increased vascular filling.</p><p class="elsevierStylePara">It is important to distinguish between the convective volume in the predilution, postdilution, mid-dilution or mixed reinfusion method. The postdilution technique is that which has been most effective in clearing uraemic toxins of a small and medium size<span class="elsevierStyleSup">18-21</span>. The main limitation in using this technique would be the intra-filter haemoconcentration that occurs and as the HD session passes, the polarisation phenomenon increases (accumulation of plasma proteins) which blocks the membrane pores, increasing the transmembrane pressure necessary to produce ultrafiltration, which decreases the effectiveness of the technique and may cause coagulation of the circuit<span class="elsevierStyleSup">22</span>. The new dialysis machines with automated infusion systems have minimised haemoconcentration problems and the number of alarms, which has maximised the convective volume. This study is a clear example of the technological advancement and it shows that the reinfusion volume may increase between 3 and 4 l per session with an automated continuous Qi control system.</p><p class="elsevierStylePara">Achieving adequate convection volumes (probably higher than 21 l per session) may be complicated in patients with limited blood flow (patients with catheters or malfunctioning vascular access). Some studies have achieved high ultrafiltration volumes using monitor optimisation systems. For example, the Gambro<span class="elsevierStyleSup">®</span> ultracontrol system in some studies allowed a higher convective volume to be achieved<span class="elsevierStyleSup">13 </span>and in others, an increase in the filtration fraction by more than 30%<span class="elsevierStyleSup">23</span>. Moreover, in the previous Fresenius 5008 monitors, to maximise the infusion rate, use of the automated manual regimen was recommended, which consisted of maintaining the automatic infusion of the Qi, achieving the initial regimen by modifying the protein and/or haematocrit monitor values, which achieved an increase in the Qi with a lower number of alarms<span class="elsevierStyleSup">14</span>; in this study, in one of the four sessions, the Qi was forced to 20 mL/min and a 2.2 l increase was achieved in the replacement volume (half of the current version). The new 5008 CorDiax version simplifies the process with a fully automated infusion system which, as this study shows, has achieved an increase in the convective volume.</p><p class="elsevierStylePara">Another aspect that has not yet been resolved is the way in which to express convective volume. We should express it in litres per session in absolute terms or relative to dry weight, by body surface area, by body mass index or, as was mentioned previously by the EuDial group, by the percentage of total filtered blood. In this study, considering that the average dialysis duration was almost five hours, the total convective volumes achieved were high, regardless of how we express them, and a significant increase was observed with the new software. The replacement volume increased from 5.3 L/h to 6.17 l/h, with the effective convective volume percentage increasing from 26.1% to 29.6% of total filtered blood. This significant difference may be important in patients who carry out short OL-HDF sessions or in those in which the Qb is limited.</p><p class="elsevierStylePara">The convection dose continues to be the major issue to be resolved in the coming years, and it is currently recommended that a total convective volume greater than 21 l per session should be achieved, based on the post-hoc analysis results of the main clinical trials, in the absence of more conclusive scientific evidence.</p><p class="elsevierStylePara"><span class="elsevierStyleBold"> </span></p><p class="elsevierStylePara"><span class="elsevierStyleBold">CONCLUSION</span></p><p class="elsevierStylePara"><span class="elsevierStyleBold"> </span></p><p class="elsevierStylePara">The change of software in the 5008 dialysis monitor has meant a 13% increase in the total convective volume. The effective convective volume percentage of total processed blood increased by 3.5%. These results were achieved without differences in arterial, venous or transmembrane pressure. This technological advancement has allowed an increase in the convective volume per session, which could lead to optimum volumes being achieved in a greater number of patients.</p><p class="elsevierStylePara"><span class="elsevierStyleBold"> </span></p><p class="elsevierStylePara"><span class="elsevierStyleBold">Conflicts of interest</span></p><p class="elsevierStylePara"><span class="elsevierStyleBold"> </span></p><p class="elsevierStylePara">Dr. Francisco Maduell has received fees as a Fresenius speaker.</p><p class="elsevierStylePara"><a href="grande/12534_16025_59935_en_t112534i.pdf1.jpg" class="elsevierStyleCrossRefs"><img src="12534_16025_59935_en_t112534i.pdf1.jpg" alt="Patients considered to be immunocompromised or immunocompetent with other underlying pathologies or risk factors "></img></a></p><p class="elsevierStylePara">Table 1. Patients considered to be immunocompromised or immunocompetent with other underlying pathologies or risk factors </p><p class="elsevierStylePara"><a href="grande/12534_16025_59936_en_t212534i2.jpg" class="elsevierStyleCrossRefs"><img src="12534_16025_59936_en_t212534i2.jpg" alt="Vaccination recommendations in adults with an underlying disease "></img></a></p><p class="elsevierStylePara">Table 2. Vaccination recommendations in adults with an underlying disease </p>" "pdfFichero" => "P1-E574-S4702-A12534-EN.pdf" "tienePdf" => true "PalabrasClave" => array:2 [ "es" => array:5 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec437259" "palabras" => array:1 [ 0 => "Trasplante renal" ] ] 1 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec437261" "palabras" => array:1 [ 0 => "Enfermedad renal crónica" ] ] 2 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec437263" "palabras" => array:1 [ 0 => "Neumococo" ] ] 3 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec437265" "palabras" => array:1 [ 0 => "Consenso sociedades" ] ] 4 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec437267" "palabras" => array:1 [ 0 => "Vacunación" ] ] ] "en" => array:5 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec437260" "palabras" => array:1 [ 0 => "Renal transplantation" ] ] 1 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec437262" "palabras" => array:1 [ 0 => "Chronic kidney disease" ] ] 2 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec437264" "palabras" => array:1 [ 0 => "Pneumococo" ] ] 3 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec437266" "palabras" => array:1 [ 0 => "Societies consensus" ] ] 4 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec437268" "palabras" => array:1 [ 0 => "Vaccination" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "es" => array:1 [ "resumen" => "<p class="elsevierStylePara">La enfermedad neumocócica invasiva (ENI) supone un grave problema en algunos grupos de riesgo: los pacientes con enfermedad renal crónica estadios 4 y 5 y aquellos con estadio 3 y tratamiento inmunosupresor, síndrome nefrótico o diabetes. Estos individuos son más susceptibles de adquirir la infección y más propensos a padecer cuadros de mayor gravedad y peor evolución. Entre las estrategias para prevenir la ENI se encuentra la vacunación, aunque las coberturas vacunales en este grupo son más bajas de lo deseable hoy en día. Actualmente, disponemos de dos vacunas para el adulto. La vacuna polisacárida (VNP23), que se emplea en mayores de 2 años de edad desde hace décadas, es la que mayor número de serotipos (23) incluye, pero no genera memoria inmunitaria, provoca un fenómeno de tolerancia inmunitaria y no actúa sobre la colonización nasofaríngea. La vacuna conjugada (VNC13) puede emplearse desde lactantes hasta la edad adulta (la indicación en mayores de 18 años ha recibido la aprobación de la Agencia Europea de Medicamentos en julio de 2013) y genera una respuesta inmunitaria más potente que la VNP23 frente a la mayoría de los 13 serotipos en ella incluidos. Las 16 sociedades científicas más directamente relacionadas con los grupos de riesgo para padecer ENI han trabajado en la discusión y elaboración de una serie de recomendaciones vacunales basadas en las evidencias científicas respecto a la vacunación antineumocócica en el adulto con condiciones y patología de base que se recogen en el documento «Consenso: Vacunación antineumocócica en el adulto con patología de base». En el presente texto se recogen las recomendaciones de vacunación para la población de enfermos renales crónicos.</p>" ] "en" => array:1 [ "resumen" => "<p class="elsevierStylePara">Invasive pneumococcal disease (IPD) is a serious problem in some risk groups: patients with stage 4 and 5 chronic kidney disease, stage 3 CKD undergoing immunosuppressive treatment, nephrotic syndrome or diabetes. These individuals are more susceptible to infections and more prone to suffering more severe and worsening symptoms. Vaccination is one of the strategies for preventing IPD, although vaccination coverage in this group at present is lower than desired. Currently, there are two vaccinations for adults. The polysaccharide vaccine (PPSV23), used for decades in patients over the age of 2, includes most serotypes (23), but it does not generate immune memory, causing the immune tolerance phenomenon and it does not act on nasopharyngeal colonisation. The conjugate vaccine (VNC13) can be used from infancy until adulthood (advice in patients over 18 years old received approval from the European Medicines Agency in July 2013) and generates a more powerful immune response than PPSV23 against the majority of the 13 serotypes that it includes. The 16 scientific societies most directly associated with the groups at risk of IPD have discussed and drafted a series of vaccination recommendations based on scientific evidence related to pneumococcal vaccination in adults with underlying conditions and pathologies, which are the subject of the document “Consensus: Pneumococcal vaccination in adults with underlying pathology”. This text sets out the vaccination recommendations for the chronic kidney disease population.</p>" ] ] "multimedia" => array:2 [ 0 => array:8 [ "identificador" => "fig1" "etiqueta" => "Tab. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "copyright" => "Elsevier España" "figura" => array:1 [ 0 => array:4 [ "imagen" => "12534_16025_59935_en_t112534i.pdf1.jpg" "Alto" => 1989 "Ancho" => 2173 "Tamanyo" => 1391950 ] ] "descripcion" => array:1 [ "en" => "Patients considered to be immunocompromised or immunocompetent with other underlying pathologies or risk factors" ] ] 1 => array:8 [ "identificador" => "fig2" "etiqueta" => "Tab. 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "copyright" => "Elsevier España" "figura" => array:1 [ 0 => array:4 [ "imagen" => "12534_16025_59936_en_t212534i2.jpg" "Alto" => 1138 "Ancho" => 2160 "Tamanyo" => 644955 ] ] "descripcion" => array:1 [ "en" => "Vaccination recommendations in adults with an underlying disease" ] ] ] "bibliografia" => array:2 [ "titulo" => "Bibliography" "seccion" => array:1 [ 0 => array:1 [ "bibliografiaReferencia" => array:31 [ 0 => array:3 [ "identificador" => "bib1" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Ficha técnica Prevenar 13. Accessed: July 15, 2013. Available at: http://www.ema.europa.eu/docs/es_ES/document_library/EPAR-Product_Information/human/001104/WC500057247.pdf." "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 1 => array:3 [ "identificador" => "bib2" "etiqueta" => "2" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Vacunación Antineumocócica para el Adulto en la Comunidad de Madrid. Comité de Expertos Asesor de Vacunas de la Comunidad de Madrid, 2012. Accessed: July 15, 2013. Available at: http://www.madrid.org/cs/Satellite?blobcol=urldata&blobheader=application/pdf&blobheadername1=Content-disposition&blobheadername2=cadena&blobheadervalue1=filename=Vacuna_an\u{AD}tineumococica_adultos_Madrid-2012.pdf&blobheadervalue2=language=es&site=PortalSalud&blobkey=id&blobtable=MungoBlobs&blobwhere=1311043153702&ssbinary=true." 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| Year/Month | Html | Total | |
|---|---|---|---|
| 2024 November | 2 | 2 | 4 |
| 2024 October | 53 | 117 | 170 |
| 2024 September | 63 | 69 | 132 |
| 2024 August | 91 | 85 | 176 |
| 2024 July | 75 | 45 | 120 |
| 2024 June | 64 | 55 | 119 |
| 2024 May | 87 | 58 | 145 |
| 2024 April | 65 | 51 | 116 |
| 2024 March | 49 | 802 | 851 |
| 2024 February | 50 | 54 | 104 |
| 2024 January | 45 | 54 | 99 |
| 2023 December | 48 | 49 | 97 |
| 2023 November | 51 | 52 | 103 |
| 2023 October | 63 | 73 | 136 |
| 2023 September | 62 | 79 | 141 |
| 2023 August | 36 | 63 | 99 |
| 2023 July | 34 | 66 | 100 |
| 2023 June | 61 | 54 | 115 |
| 2023 May | 51 | 65 | 116 |
| 2023 April | 50 | 37 | 87 |
| 2023 March | 71 | 46 | 117 |
| 2023 February | 52 | 38 | 90 |
| 2023 January | 34 | 54 | 88 |
| 2022 December | 68 | 52 | 120 |
| 2022 November | 70 | 48 | 118 |
| 2022 October | 66 | 64 | 130 |
| 2022 September | 48 | 50 | 98 |
| 2022 August | 69 | 52 | 121 |
| 2022 July | 73 | 45 | 118 |
| 2022 June | 59 | 39 | 98 |
| 2022 May | 62 | 44 | 106 |
| 2022 April | 106 | 63 | 169 |
| 2022 March | 70 | 80 | 150 |
| 2022 February | 48 | 58 | 106 |
| 2022 January | 35 | 54 | 89 |
| 2021 December | 84 | 52 | 136 |
| 2021 November | 70 | 58 | 128 |
| 2021 October | 51 | 53 | 104 |
| 2021 September | 50 | 58 | 108 |
| 2021 August | 39 | 55 | 94 |
| 2021 July | 44 | 36 | 80 |
| 2021 June | 62 | 34 | 96 |
| 2021 May | 42 | 37 | 79 |
| 2021 April | 105 | 61 | 166 |
| 2021 March | 87 | 41 | 128 |
| 2021 February | 46 | 39 | 85 |
| 2021 January | 56 | 31 | 87 |
| 2020 December | 41 | 22 | 63 |
| 2020 November | 43 | 19 | 62 |
| 2020 October | 35 | 23 | 58 |
| 2020 September | 24 | 15 | 39 |
| 2020 August | 38 | 10 | 48 |
| 2020 July | 39 | 14 | 53 |
| 2020 June | 31 | 17 | 48 |
| 2020 May | 45 | 14 | 59 |
| 2020 April | 32 | 26 | 58 |
| 2020 March | 31 | 17 | 48 |
| 2020 February | 42 | 26 | 68 |
| 2020 January | 43 | 18 | 61 |
| 2019 December | 48 | 25 | 73 |
| 2019 November | 52 | 32 | 84 |
| 2019 October | 31 | 31 | 62 |
| 2019 September | 31 | 32 | 63 |
| 2019 August | 25 | 20 | 45 |
| 2019 July | 41 | 25 | 66 |
| 2019 June | 26 | 21 | 47 |
| 2019 May | 22 | 27 | 49 |
| 2019 April | 78 | 53 | 131 |
| 2019 March | 41 | 31 | 72 |
| 2019 February | 28 | 30 | 58 |
| 2019 January | 51 | 17 | 68 |
| 2018 December | 108 | 48 | 156 |
| 2018 November | 172 | 25 | 197 |
| 2018 October | 196 | 17 | 213 |
| 2018 September | 103 | 14 | 117 |
| 2018 August | 48 | 12 | 60 |
| 2018 July | 56 | 18 | 74 |
| 2018 June | 54 | 15 | 69 |
| 2018 May | 45 | 11 | 56 |
| 2018 April | 62 | 15 | 77 |
| 2018 March | 43 | 12 | 55 |
| 2018 February | 51 | 12 | 63 |
| 2018 January | 40 | 12 | 52 |
| 2017 December | 44 | 12 | 56 |
| 2017 November | 47 | 8 | 55 |
| 2017 October | 53 | 11 | 64 |
| 2017 September | 43 | 23 | 66 |
| 2017 August | 41 | 18 | 59 |
| 2017 July | 29 | 10 | 39 |
| 2017 June | 46 | 10 | 56 |
| 2017 May | 36 | 12 | 48 |
| 2017 April | 44 | 18 | 62 |
| 2017 March | 34 | 10 | 44 |
| 2017 February | 47 | 19 | 66 |
| 2017 January | 14 | 13 | 27 |
| 2016 December | 100 | 16 | 116 |
| 2016 November | 116 | 14 | 130 |
| 2016 October | 161 | 22 | 183 |
| 2016 September | 222 | 9 | 231 |
| 2016 August | 270 | 7 | 277 |
| 2016 July | 290 | 15 | 305 |
| 2016 June | 182 | 0 | 182 |
| 2016 May | 189 | 0 | 189 |
| 2016 April | 199 | 0 | 199 |
| 2016 March | 201 | 0 | 201 |
| 2016 February | 264 | 0 | 264 |
| 2016 January | 204 | 0 | 204 |
| 2015 December | 245 | 0 | 245 |
| 2015 November | 247 | 0 | 247 |
| 2015 October | 197 | 0 | 197 |
| 2015 September | 166 | 0 | 166 |
| 2015 August | 175 | 0 | 175 |
| 2015 July | 163 | 0 | 163 |
| 2015 June | 103 | 0 | 103 |
| 2015 May | 150 | 0 | 150 |
| 2015 April | 44 | 0 | 44 |
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