Editorial
Sublingual Immunotherapies: The more we know, the more we need to know
Antonio Martínez-Gimeno
Department of Pediatrics, Hospital Virgen de la Salud, Toledo, Spain
Read
1923
Timeswas read the article
690
Total PDF
1233
Total HTML
Share statistics
array:22 [ "pii" => "S0301054613001651" "issn" => "03010546" "doi" => "10.1016/j.aller.2013.06.001" "estado" => "S300" "fechaPublicacion" => "2013-07-01" "aid" => "531" "copyright" => "SEICAP" "copyrightAnyo" => "2013" "documento" => "simple-article" "crossmark" => 0 "subdocumento" => "edi" "cita" => "Allergol Immunopathol (Madr). 2013;41:213-5" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:2 [ "total" => 1104 "formatos" => array:3 [ "EPUB" => 8 "HTML" => 714 "PDF" => 382 ] ] "itemSiguiente" => array:18 [ "pii" => "S0301054612002236" "issn" => "03010546" "doi" => "10.1016/j.aller.2012.07.004" "estado" => "S300" "fechaPublicacion" => "2013-07-01" "aid" => "427" "copyright" => "SEICAP" "documento" => "article" "crossmark" => 0 "subdocumento" => "fla" "cita" => "Allergol Immunopathol (Madr). 2013;41:216-24" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:2 [ "total" => 1551 "formatos" => array:3 [ "EPUB" => 8 "HTML" => 1112 "PDF" => 431 ] ] "en" => array:12 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Original article</span>" "titulo" => "The contribution of sublingual immunotherapy to the achievement of control in birch-related mild persistent asthma: A real-life randomised trial" "tienePdf" => "en" "tieneTextoCompleto" => "en" "tieneResumen" => "en" "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "216" "paginaFinal" => "224" ] ] "contieneResumen" => array:1 [ "en" => true ] "contieneTextoCompleto" => array:1 [ "en" => true ] "contienePdf" => array:1 [ "en" => true ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1609 "Ancho" => 3090 "Tamanyo" => 236684 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Study design.</p>" ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "M. Marogna, C. Braidi, M.E. Bruno, C. Colombo, F. Colombo, A. Massolo, L. Palumbo, E. Compalati" "autores" => array:8 [ 0 => array:2 [ "nombre" => "M." "apellidos" => "Marogna" ] 1 => array:2 [ "nombre" => "C." "apellidos" => "Braidi" ] 2 => array:2 [ "nombre" => "M.E." "apellidos" => "Bruno" ] 3 => array:2 [ "nombre" => "C." "apellidos" => "Colombo" ] 4 => array:2 [ "nombre" => "F." "apellidos" => "Colombo" ] 5 => array:2 [ "nombre" => "A." "apellidos" => "Massolo" ] 6 => array:2 [ "nombre" => "L." "apellidos" => "Palumbo" ] 7 => array:2 [ "nombre" => "E." "apellidos" => "Compalati" ] ] ] ] ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0301054612002236?idApp=UINPBA00004N" "url" => "/03010546/0000004100000004/v1_201307160011/S0301054612002236/v1_201307160011/en/main.assets" ] "en" => array:10 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Editorial</span>" "titulo" => "Sublingual Immunotherapies: The more we know, the more we need to know" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "213" "paginaFinal" => "215" ] ] "autores" => array:1 [ 0 => array:3 [ "autoresLista" => "Antonio Martínez-Gimeno" "autores" => array:1 [ 0 => array:3 [ "nombre" => "Antonio" "apellidos" => "Martínez-Gimeno" "email" => array:1 [ 0 => "amgimeno@gmail.com" ] ] ] "afiliaciones" => array:1 [ 0 => array:2 [ "entidad" => "Department of Pediatrics, Hospital Virgen de la Salud, Toledo, Spain" "identificador" => "aff0005" ] ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall">Sublingual Immunotherapy (SLIT), as a general term, comprises a large group of different medicinal products that share a common route of administration but have different formulation, allergen standardisation, doses and many other relevant differences, including their regulatory status. According to this last feature, the medicinal products included in SLIT, as a medicinal product class, can be loosely classified into three subgroups. The first subgroup includes the small minority that have proceeded through a standard drug development procedure and have obtained a Marketing Authorization according to the Directive 2001/83/EC as amended by the European regulatory agency (EMEA) like any other drug, i.e., the <span class="elsevierStyleBold">standard drug Sublingual Immunotherapies</span>, which have the strongest evidence support based on large-scale randomised placebo-controlled clinical trials in adults and children and can be considered the elite of the SLIT class. The second subgroup includes the large majority of Sublingual Immunotherapies approved in European Countries by local Regulatory Agencies as immunological products manufactured by authorised immunological/pharmaceutical companies on a named-patient basis specifically for sublingual route administration, which we shall describe as the <span class="elsevierStyleBold">Southern Europe Style Sublingual Immunotherapies</span>. The evidence supporting the efficacy and safety of the medicinal products included in this group is generally scarce on an individual basis, but, as a group, there are a good number of systematic reviews and a metaanalysis that support their clinical use.<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1–3</span></a> In Scandinavian countries, allergen extracts have only been available as standard drugs for decades and no market exist for named-patients products, including SLIT.<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> The third group is the <span class="elsevierStyleBold">USA Style sublingual off-label immunotherapies</span> which comprises the aqueous preparations formulated in most cases in the allergist office on a named-patient basis, often containing several different antigens, and approved only for subcutaneous administration but prescribed off-label, i.e., for a non-approved use, for sublingual administration.<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> In North America only the third subgroup of SLIT medicinal products are available for clinical use. This simple, straightforward classification may explain why the use of SLIT medicinal products is so different around the world. In USA, only 6–11% of allergists use SLIT,<a class="elsevierStyleCrossRefs" href="#bib0020"><span class="elsevierStyleSup">4,5</span></a> whilst in Europe they represent approximately 45% of the total Specific Immunotherapy (SIT) prescribed, with large differences between countries: in northern Europe almost none and only standard drug SLIT. In Germany, it is 25% and in Southern Europe, up to 80%. Curiously, the standard drug SLIT subgroup is not among the most prescribed SLIT medicinal products, despite strong supporting evidence.<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">In the current issue of <span class="elsevierStyleItalic">Allergologia et Immunopathologia</span>, Marogna et al. report the results of an interesting randomised but open-labelled clinical trial assessing the contribution of one of the medicinal products included in what I have called <span class="elsevierStyleItalic">Southern Europe Style Sublingual Immunotherapies</span> (i.e., a medicinal product approved by Italian Regulatory Agency on a named-patient basis, although with a standard tablet formulation containing a carbamylated monomerid allergoid from birch pollen<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a> [Lais<span class="elsevierStyleSup">®</span>, Lofarma S.p.A., Milan, Italy]) to the achievement of asthma control in adult patients with mild persistent seasonal asthma monosensitised to birch pollen not controlled during the run-in season by a step-2 standard treatment with budesonide 400<span class="elsevierStyleHsp" style=""></span>mcg inhaled daily.<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a> The study design has some remarkable key features: it is a long-term clinical trial prospectively comprising four seasons, one for run-in and three for active treatment; the investigational treatment (adding Lais<span class="elsevierStyleSup">®</span> to the step-2 budesonide dose that had previously failed to control asthma) is put in direct comparison to standard step-3 treatment, i.e. doubling or quadrupling the budesonide dose or adding a second controller drug, montelukast, to the previous step-2 budesonide dose. In this way, the authors have directly compared adding the SLIT medicinal product as an additional controller with three other common increases in drug treatment. The primary end-point is a solid, well validated and clinically relevant one, the mean monthly Asthma Control Test results, with some other relevant secondary end-points, including spirometry results. The final results are outstanding: the group of patients (<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>21) that received three pre-coseasonal courses of Lais<span class="elsevierStyleSup">®</span> along with budesonide 400<span class="elsevierStyleHsp" style=""></span>mcg did exceedingly better than the other three groups (<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>21, respectively). The mean (±SD) ACT value after three seasons of treatment was 24<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>0.2, reaching almost the maximum value (25), and leaving almost no room for further improvement, compared with 17.2 to 18.4 in the other groups. Mean FEV1 raised from a basal predicted value of 85% to an excellent 103% after the third treatment season compared to 90–96% in the other groups. These results suggests that adding Lais<span class="elsevierStyleSup">®</span> to adult asthmatic patients monosensitised to birch pollen who are not adequately controlled by standard step-2 treatment with budesonide 400<span class="elsevierStyleHsp" style=""></span>mcg daily is superior to standard alternatives of increasing the budesonide dose or adding a second controller. These results are very relevant because they support the inclusion of the experimental medicinal product (Lais<span class="elsevierStyleSup">®</span>) in the standard step-wise pharmacological treatment in this selected adult population, who, incidentally, were selected by traditional allergic evaluation with prick test and serum specific IgE against birch pollen and not using molecular diagnostic procedures, as in most if not all clinical trials on SIT.</p><p id="par0015" class="elsevierStylePara elsevierViewall">However, this randomised clinical trial has some important weaknesses. The lack of blinding may certainly be a source of bias, partially corrected by an appropriate randomisation procedure. The open label nature of the study, euphemistically referred to by the authors as a “real-life randomised trial” may be an obstacle to include this trial in some high quality metaanalysis, but not all, which usually consider only double-blind randomised clinical trials of high quality. For instance, using the Jadad scoring system (from 0 to 5), only two points would be obtained by this trial. Also, the European Guidelines for the clinical development of products for specific immunotherapy for the treatment of allergic diseases<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a> establish a double-blind placebo-controlled design to obtain evidence of efficacy and safety, even in children,<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a> for marketing authorisation purposes. “Real life” designs, i.e. open-labelled clinical trials, are only justified when a very large population is needed to obtain valid conclusions and blinding or placebo use is particularly difficult, which is not the case. As in most of the <span class="elsevierStyleItalic">Southern Europe Style SLIT clinical trials</span>, the number of participants is rather low (21 per treatment group), consistently with the one centre nature of the clinical trial. Compared with multicentre randomised double-blind placebo-controlled clinical trials from development programmes of <span class="elsevierStyleItalic">standard drug SLIT</span>, such as that recently published by Creticos et al., (<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>784, double-blind, placebo-controlled in patients with ragweed allergy)<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a> the number of participants of the study of Marogna et al. seem low. However, due to the large beneficial effect of the experimental treatment, the difference between the experimental group and control groups reached statistical significance.</p><p id="par0020" class="elsevierStylePara elsevierViewall">It is a common statement that the efficacy of SLIT in allergic asthma is well supported by systematic reviews and metaanalysis. So, do we need more clinical trials on the subject like the one we are commenting on? The answer is yes, we certainly do. The title of a recently published editorial in the <span class="elsevierStyleItalic">Journal of the American Medical Association</span> commenting on one of the latest metaanalyses on the subject<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> is quite clear in this respect: Is sublingual immunotherapy Ready for Use in the United States?<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a> And the conclusion is: no, it is not. However, from the European point of view, SLIT is ready for use and we have been using it lawfully for many years. But we do need to know more about <span class="elsevierStyleItalic">each medicinal product</span> of this class and keep on advancing to the ideal situation in which <span class="elsevierStyleItalic">each SLIT medicinal product</span> has a full development programme supporting its approval, including their Pediatric Investigation Plans for children<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a> and complete safety records.<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a> This is why I heartily welcome the paper by Marogna et al. and encourage immunotherapy companies to further develop their SLIT medicinal products following their Regulatory Agencies guidelines and not relying on data obtained with other SLIT medicinal products all mixed up in heterogeneous metaanalyses and systematic revisions. That is why I keep on using the term Sublingual Immunotherapies (in plural). The time for standard individual approval and beyond has come.<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a></p></span>" "pdfFichero" => "main.pdf" "tienePdf" => true "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:14 [ 0 => array:3 [ "identificador" => "bib0005" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Sublingual immunotherapy for the treatment of allergic rhinoconjunctivitis and asthma. A systematic review" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "S.Y. Lin" 1 => "N. Erekosima" 2 => "J. Kim" 3 => "M. Ramanathan" 4 => "C. Suárez-Cuervo" 5 => "Y. Chelladurai" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1001/jama.2013.2049" "Revista" => array:6 [ "tituloSerie" => "JAMA" "fecha" => "2013" "volumen" => "309" "paginaInicial" => "1278" "paginaFinal" => "1288" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/23532243" "web" => "Medline" ] ] ] ] ] ] ] ] 1 => array:3 [ "identificador" => "bib0010" "etiqueta" => "2" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Pediatric sublingual immunotherapy efficacy: evidence analysis 2009–2012" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "D. Larenas-Linnemann" 1 => "M. Blaiss" 2 => "H.P. Van Bever" 3 => "E. Compalati" 4 => "C.E. Baena-Cagnani" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.anai.2013.02.017" "Revista" => array:6 [ "tituloSerie" => "Ann Allergy Asthma Immunol" "fecha" => "2013" "volumen" => "110" "paginaInicial" => "402" "paginaFinal" => "415" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/23706708" "web" => "Medline" ] ] ] ] ] ] ] ] 2 => array:3 [ "identificador" => "bib0015" "etiqueta" => "3" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Allergen-specific immunotherapy: update on immunological mechanisms" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "M. Álvaro" 1 => "J. Sancha" 2 => "H. Larramona" 3 => "J.M. Lucas" 4 => "M. Mesa" 5 => "A.I. Tabar" ] ] ] ] ] "host" => array:2 [ 0 => array:1 [ "Revista" => array:2 [ "tituloSerie" => "Allergol Immunopathol (Madrid)" "fecha" => "2013" ] ] 1 => array:1 [ "WWW" => array:1 [ "link" => "http://dx.doi.org/10.1016/j.aller.2012.07.018" ] ] ] ] ] ] 3 => array:3 [ "identificador" => "bib0020" "etiqueta" => "4" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Comparison of allergen immunotherapy practice patterns in the United States and Europe" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "L. Cox" 1 => "L. Jacobsen" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/S1081-1206(10)60259-1" "Revista" => array:6 [ "tituloSerie" => "Ann Allergy Asthma Immunol" "fecha" => "2009" "volumen" => "103" "paginaInicial" => "451" "paginaFinal" => "460" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/20084837" "web" => "Medline" ] ] ] ] ] ] ] ] 4 => array:3 [ "identificador" => "bib0025" "etiqueta" => "5" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Perception and practice of sublingual immunotherapy among practicing allergists in the United States: a follow-up survey" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "J.M. Sikora" 1 => "M.S. Tankersley" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.anai.2012.12.014" "Revista" => array:6 [ "tituloSerie" => "Ann Allergy Asthma Immunol" "fecha" => "2013" "volumen" => "110" "paginaInicial" => "194" "paginaFinal" => "197" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/23548531" "web" => "Medline" ] ] ] ] ] ] ] ] 5 => array:3 [ "identificador" => "bib0030" "etiqueta" => "6" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Carbamylated monomeric allergoids as a therapeutic option for sublingual immunotherapy of dust mite and grass pollen induced allergic rhinoconjunctivitis: a systematic review of published trials with a metaanalysis of treatment using Lais<span class="elsevierStyleSup">®</span> tablets" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "R. Mösges" 1 => "B. Ritter" 2 => "G. Kayoko" 3 => "D. Passali" 4 => "S. Allekotte" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "Acta Dermatoven APA" "fecha" => "2010" "volumen" => "19" "paginaInicial" => "3" "paginaFinal" => "10" ] ] ] ] ] ] 6 => array:3 [ "identificador" => "bib0035" "etiqueta" => "7" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "The contribution of sublingual immunotherapy to the achievement of control in birch-related mild persistent asthma: a real life randomized trial" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "M. Marogna" 1 => "C. Braidi" 2 => "M.E. Bruno" 3 => "C. Colombo" 4 => "F. Colombo" 5 => "A. Massolo" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "Allergol Immunopathol (Madrid)" "fecha" => "2013" "volumen" => "41" "paginaInicial" => "216" "paginaFinal" => "224" ] ] ] ] ] ] 7 => array:3 [ "identificador" => "bib0040" "etiqueta" => "8" "referencia" => array:1 [ 0 => array:1 [ "referenciaCompleta" => "Guidelines on the clinical development of products for specific immunotherapy for the treatment of allergic diseases. Available at <a id="intr0010" class="elsevierStyleInterRef" href="http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500003605.pdf">http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500003605.pdf</a>; [accessed on 09.06.13]." ] ] ] 8 => array:3 [ "identificador" => "bib0045" "etiqueta" => "9" "referencia" => array:1 [ 0 => array:1 [ "referenciaCompleta" => "EMA/PDCO Standard Paediatric Investigation plan for Allergen Products for Specific Immunotherapy. Revision 3. EMA/PDCO/737605/200909. Available at <a id="intr0015" class="elsevierStyleInterRef" href="http://www.ema.europa.eu/docs/en_GB/document_library/Regulatory_and_procedural_guideline/2009/11/WC500015814.pdf">http://www.ema.europa.eu/docs/en_GB/document_library/Regulatory_and_procedural_guideline/2009/11/WC500015814.pdf</a>; [accessed on 09.06.13]." ] ] ] 9 => array:3 [ "identificador" => "bib0050" "etiqueta" => "10" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Randomized controlled trial of a ragweed allergy immunotherapy tablet in North American and European Adults" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "P.S. Creticos" 1 => "J. Maloney" 2 => "D.I. Bernstein" 3 => "T. Casale" 4 => "A. Kaur" 5 => "R. Fisher" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.jaci.2013.03.019" "Revista" => array:6 [ "tituloSerie" => "J Allergy Clin Immunol" "fecha" => "2013" "volumen" => "131" "paginaInicial" => "1342" "paginaFinal" => "1349" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/23622121" "web" => "Medline" ] ] ] ] ] ] ] ] 10 => array:3 [ "identificador" => "bib0055" "etiqueta" => "11" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Is sublingual immunotherapy ready for use in the United States?" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "H.S. Nelson" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1001/jama.2013.2739" "Revista" => array:6 [ "tituloSerie" => "JAMA" "fecha" => "2013" "volumen" => "309" "paginaInicial" => "1297" "paginaFinal" => "1298" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/23532248" "web" => "Medline" ] ] ] ] ] ] ] ] 11 => array:3 [ "identificador" => "bib0060" "etiqueta" => "12" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Perspectives on allergen-specific immunotherapy in childhood: an EAACI position statement" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "M.A. Calderon" 1 => "R.G. van Wijk" 2 => "I. Eichler" 3 => "P.M. Maricardi" 4 => "E.M. Varga" 5 => "M.V. Kopp" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1111/j.1399-3038.2012.01313.x" "Revista" => array:6 [ "tituloSerie" => "Pediatr Allergy Immunol" "fecha" => "2012" "volumen" => "23" "paginaInicial" => "300" "paginaFinal" => "306" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/22594930" "web" => "Medline" ] ] ] ] ] ] ] ] 12 => array:3 [ "identificador" => "bib0065" "etiqueta" => "13" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Grading local side effects of sublingual immunotherapy for respiratory allergy: speaking the same language" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "G. Passalacqua" 1 => "C.E. Baena-Cagnani" 2 => "J. Bousquet" 3 => "G.W. Canonica" 4 => "T.B. Casale" 5 => "L. Cox" ] ] ] ] ] "host" => array:2 [ 0 => array:1 [ "Revista" => array:3 [ "tituloSerie" => "J Allergy Clin Immunol" "fecha" => "2013" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/10329805" "web" => "Medline" ] ] ] ] 1 => array:1 [ "WWW" => array:1 [ "link" => "http://dx.doi.org/10.1016/j.jaci.2013.03.039" ] ] ] ] ] ] 13 => array:3 [ "identificador" => "bib0070" "etiqueta" => "14" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "From meta-analysis to registration and beyond" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "M.A. Calderón" 1 => "T.B. Casale" 2 => "A. Togias" 3 => "J. Bousquet" 4 => "S. Durham" 5 => "P. Demoly" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.jaci.2010.08.024" "Revista" => array:6 [ "tituloSerie" => "J Allergy Clin Immunol" "fecha" => "2011" "volumen" => "127" "paginaInicial" => "30" "paginaFinal" => "38" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/20965551" "web" => "Medline" ] ] ] ] ] ] ] ] ] ] ] ] ] "idiomaDefecto" => "en" "url" => "/03010546/0000004100000004/v1_201307160011/S0301054613001651/v1_201307160011/en/main.assets" "Apartado" => array:4 [ "identificador" => "5552" "tipo" => "SECCION" "en" => array:2 [ "titulo" => "Editorial" "idiomaDefecto" => true ] "idiomaDefecto" => "en" ] "PDF" => "https://static.elsevier.es/multimedia/03010546/0000004100000004/v1_201307160011/S0301054613001651/v1_201307160011/en/main.pdf?idApp=UINPBA00004N&text.app=https://www.elsevier.es/" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0301054613001651?idApp=UINPBA00004N" ]
| Year/Month | Html | Total | |
|---|---|---|---|
| 2024 November | 1 | 1 | 2 |
| 2024 October | 11 | 2 | 13 |
| 2024 September | 7 | 1 | 8 |
| 2024 August | 6 | 3 | 9 |
| 2024 July | 8 | 1 | 9 |
| 2024 June | 4 | 2 | 6 |
| 2024 May | 11 | 4 | 15 |
| 2024 April | 7 | 2 | 9 |
| 2024 March | 10 | 2 | 12 |
| 2024 February | 7 | 5 | 12 |
| 2024 January | 23 | 1 | 24 |
| 2023 December | 17 | 8 | 25 |
| 2023 November | 7 | 11 | 18 |
| 2023 October | 12 | 12 | 24 |
| 2023 September | 19 | 0 | 19 |
| 2023 August | 16 | 5 | 21 |
| 2023 July | 19 | 4 | 23 |
| 2023 June | 7 | 2 | 9 |
| 2023 May | 9 | 6 | 15 |
| 2023 April | 8 | 1 | 9 |
| 2023 March | 5 | 1 | 6 |
| 2023 February | 16 | 2 | 18 |
| 2023 January | 20 | 8 | 28 |
| 2022 December | 12 | 6 | 18 |
| 2022 November | 16 | 8 | 24 |
| 2022 October | 9 | 10 | 19 |
| 2022 September | 9 | 5 | 14 |
| 2022 August | 14 | 14 | 28 |
| 2022 July | 10 | 8 | 18 |
| 2022 June | 8 | 4 | 12 |
| 2022 May | 14 | 13 | 27 |
| 2022 April | 12 | 9 | 21 |
| 2022 March | 10 | 9 | 19 |
| 2022 February | 5 | 8 | 13 |
| 2022 January | 17 | 8 | 25 |
| 2021 December | 9 | 9 | 18 |
| 2021 November | 10 | 11 | 21 |
| 2021 October | 13 | 7 | 20 |
| 2021 September | 10 | 13 | 23 |
| 2021 August | 7 | 4 | 11 |
| 2021 July | 7 | 11 | 18 |
| 2021 June | 13 | 15 | 28 |
| 2021 May | 11 | 10 | 21 |
| 2021 April | 22 | 12 | 34 |
| 2021 March | 15 | 7 | 22 |
| 2021 February | 8 | 10 | 18 |
| 2021 January | 7 | 8 | 15 |
| 2020 December | 1 | 0 | 1 |
| 2020 November | 0 | 1 | 1 |
| 2020 August | 0 | 1 | 1 |
| 2020 July | 0 | 1 | 1 |
| 2020 May | 0 | 1 | 1 |
| 2020 April | 0 | 1 | 1 |
| 2019 December | 0 | 2 | 2 |
| 2019 November | 0 | 4 | 4 |
| 2019 September | 0 | 1 | 1 |
| 2019 August | 0 | 1 | 1 |
| 2019 July | 0 | 7 | 7 |
| 2019 June | 0 | 4 | 4 |
| 2019 May | 0 | 10 | 10 |
| 2018 March | 3 | 0 | 3 |
| 2018 February | 2 | 1 | 3 |
| 2017 December | 4 | 0 | 4 |
| 2017 November | 2 | 1 | 3 |
| 2017 October | 7 | 1 | 8 |
| 2017 September | 3 | 1 | 4 |
| 2017 August | 12 | 0 | 12 |
| 2017 July | 8 | 1 | 9 |
| 2017 June | 16 | 2 | 18 |
| 2017 May | 15 | 3 | 18 |
| 2017 April | 12 | 1 | 13 |
| 2017 March | 12 | 25 | 37 |
| 2017 February | 13 | 4 | 17 |
| 2017 January | 9 | 0 | 9 |
| 2016 December | 8 | 6 | 14 |
| 2016 November | 18 | 8 | 26 |
| 2016 October | 20 | 6 | 26 |
| 2016 September | 11 | 6 | 17 |
| 2016 August | 15 | 2 | 17 |
| 2016 July | 7 | 1 | 8 |
| 2016 June | 14 | 4 | 18 |
| 2016 May | 14 | 16 | 30 |
| 2016 April | 10 | 8 | 18 |
| 2016 March | 12 | 14 | 26 |
| 2016 February | 9 | 17 | 26 |
| 2016 January | 10 | 17 | 27 |
| 2015 December | 6 | 12 | 18 |
| 2015 November | 12 | 16 | 28 |
| 2015 October | 17 | 10 | 27 |
| 2015 September | 6 | 9 | 15 |
| 2015 August | 9 | 3 | 12 |
| 2015 July | 7 | 3 | 10 |
| 2015 June | 2 | 1 | 3 |
| 2015 May | 6 | 1 | 7 |
| 2015 April | 8 | 13 | 21 |
| 2015 March | 12 | 11 | 23 |
| 2015 February | 7 | 6 | 13 |
| 2015 January | 13 | 6 | 19 |
| 2014 December | 18 | 8 | 26 |
| 2014 November | 11 | 3 | 14 |
| 2014 October | 21 | 7 | 28 |
| 2014 September | 21 | 2 | 23 |
| 2014 August | 7 | 5 | 12 |
| 2014 July | 11 | 5 | 16 |
| 2014 April | 1 | 0 | 1 |
| 2014 March | 40 | 9 | 49 |
| 2014 February | 30 | 10 | 40 |
| 2014 January | 33 | 9 | 42 |
| 2013 December | 31 | 7 | 38 |
| 2013 November | 26 | 10 | 36 |
| 2013 October | 29 | 9 | 38 |
| 2013 September | 29 | 10 | 39 |
| 2013 August | 18 | 10 | 28 |
| 2013 July | 17 | 13 | 30 |
Show all
