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A role for measurement of nasal IgE antibodies in diagnosis of Alternaria-induced rhinitis in children
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Fuiano, S. Fusilli, C. Incorvaia" "autores" => array:3 [ 0 => array:4 [ "nombre" => "N." "apellidos" => "Fuiano" "email" => array:1 [ 0 => "fuiano50@tin.it" ] "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">¿</span>" "identificador" => "cor0005" ] ] ] 1 => array:3 [ "nombre" => "S." "apellidos" => "Fusilli" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0010" ] ] ] 2 => array:3 [ "nombre" => "C." "apellidos" => "Incorvaia" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">c</span>" "identificador" => "aff0015" ] ] ] ] "afiliaciones" => array:3 [ 0 => array:3 [ "entidad" => "Paediatric Allergy Service, ASL Fg, San Severo, Foggia, Italy" "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Health Service IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Foggia, Italy" "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0010" ] 2 => array:3 [ "entidad" => "Allergy/Pulmonary rehabilitation, ICP Hospital, Milan, Italy" "etiqueta" => "<span class="elsevierStyleSup">c</span>" "identificador" => "aff0015" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Respiratory allergy with rhinitis and/or asthma is caused by clinical sensitisation to environmental inhalant allergens. Among these allergens, the importance of fungal spores has long been scantily investigated. However, recent studies have demonstrated that the prevalence of fungal sensitisation is higher than believed. As regards studies conducted in Europe, a study sponsored by the Spanish Society of Allergy and Clinical Immunology found that 9.5% of patients who had been visited due to suspected respiratory allergy were found to be sensitised to <span class="elsevierStyleItalic">Alternaria</span> or <span class="elsevierStyleItalic">Cladosporium</span>.<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> In the survey promoted by the European Academy of Allergy and Clinical Immunology (EAACI) and conducted in seven countries – Spain, Portugal, Italy, Greece, Austria, Switzerland, and Germany – the prevalence of positive tests to the two moulds ranged from 3% in Portugal to 20% in Spain.<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> Other investigations were conducted in Finland, where a prevalence of positive skin prick test (SPT) corresponding to 2.8% for <span class="elsevierStyleItalic">Alternaria</span> and to 2.7% for <span class="elsevierStyleItalic">Cladosporium</span> were detected,<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> and, very recently, in France. This latest study was addressed only to <span class="elsevierStyleItalic">Alternaria</span> sensitisation and included a population of 6,726 children, of whom 2.8% had a positive result to <span class="elsevierStyleItalic">Alternaria</span> and to other allergens, while 0.8% were mono-sensitised to <span class="elsevierStyleItalic">Alternaria</span>.<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">The clinical expression of sensitisation to <span class="elsevierStyleItalic">Alternaria</span> may include rhinitis, asthma, or both, with rhinitis or asthma prevailing in the different studies.<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2–5</span></a> However, sensitisation in general is not always detected by SPT and in vitro IgE measurement. In fact, it has been long known<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a> and recently confirmed<a class="elsevierStyleCrossRefs" href="#bib0035"><span class="elsevierStyleSup">7,8</span></a> that some subjects with rhinitis and negative skin tests may have IgE only in the nasal mucosa, due to an exclusive local production.</p><p id="par0015" class="elsevierStylePara elsevierViewall">We evaluated the local production of IgE by performing a nasal IgE test on children with rhinitis occurring during the period of the year when <span class="elsevierStyleItalic">Alternaria</span> spores were present.</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Methods</span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Patients</span><p id="par0020" class="elsevierStylePara elsevierViewall">From children referred for suspected allergy to our Paediatric Allergy Service, all subjects reporting rhinitis symptoms such as sneezing, nasal itching, rhinorrhoea, and nasal obstruction over a period of at least two years in the periods corresponding to the presence of <span class="elsevierStyleItalic">Alternaria</span> spores in our area – from the 3<span class="elsevierStyleSup">rd</span> week of May to the 1<span class="elsevierStyleSup">st</span> week of July and from the 3<span class="elsevierStyleSup">rd</span> week of August to the 2<span class="elsevierStyleSup">nd</span> week of October<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a> – were included in the study.</p><p id="par0025" class="elsevierStylePara elsevierViewall">All patients underwent SPT with a standard panel of inhalant allergens (Stallergenes, Milan, Italy) and, in the same session, measurement of specific nasal IgE by an already validated<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a> commercial kit (Biomicron, Turin, Italy). Nasal provocation test with <span class="elsevierStyleItalic">Alternaria</span> was performed in December, when <span class="elsevierStyleItalic">Alternaria</span> spores were by then absent in the atmosphere.</p><p id="par0030" class="elsevierStylePara elsevierViewall">All children's parents gave an informal consent.</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Nasal IgE test</span><p id="par0035" class="elsevierStylePara elsevierViewall">Nasal IgE test (NT) was performed by the technique originally described by Marcucci et al.<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a> In brief, the allergen coupled cellulose derivative was placed in a two-hole applicator strip covered with a permeable membrane (to avoid the adhesion of nasal mucus on the substrate) and positioned in the above-posterior tract of the internal ostium for 10<span class="elsevierStyleHsp" style=""></span>minutes. The results were subsequently read according to a colorimetric reaction and expressed in a scale from 0 (negative) to 4 (highly positive), according to a calibration curve<span class="elsevierStyleBold">.</span></p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Nasal provocation test (NPT)</span><p id="par0040" class="elsevierStylePara elsevierViewall">NPT was performed using the <span class="elsevierStyleItalic">Alternaria</span> extract Alyostal (Stallergenes) titrated in 100 Index of Reactivity (IR). The test started by administering physiological solution in one nostril and then 100<span class="elsevierStyleHsp" style=""></span>μl. of increasing concentrations of the extract every 20<span class="elsevierStyleHsp" style=""></span>minutes alternating between both nostrils. The concentrations used were 0.2, 0.5, 0.8, 1.8, and 2.8 IR. After each administration the nasal symptoms (nasal itching and sneezing, runny nose, and nasal blockage) were evaluated by a scoring system attributing 1 point to mild, 2 points to moderate, and 3 points to severe symptoms.<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a></p><p id="par0045" class="elsevierStylePara elsevierViewall">All NPTs were performed by the same operator (N.F.) in a symptom-free period when no drug which could have interfered with the nasal response to the specific allergen was being used.</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Statistical analysis</span><p id="par0050" class="elsevierStylePara elsevierViewall">Data are presented as percentage and as mean<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>sd for qualitative and quantitative variables, respectively. Statistical analysis was performed using χ<span class="elsevierStyleSup">2</span> test and Z test to compare the proportions of patients with NT / NPT positivity and SPT / NT positivity, respectively. Statistical significance was assumed for p<span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>0.05 and, for Z test two tails.</p></span></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Results</span><p id="par0055" class="elsevierStylePara elsevierViewall">Fifty-six children, 30 males and 26 females of age ranging between 50 and 216 months (mean age 137.5<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>43.2 months, median age 137.5 months) were included in the study. <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a> shows the results of SPT and NT. Twenty subjects (37.5%) were positive to SPT and 45 (80.3%) were positive to NT. In particular, 11 subjects (19.6%) had a positive SPT and a negative NT; 36 (64.3%) had a negative SPT and a positive NT; and 9 (16.1%) were positive to both tests.</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0060" class="elsevierStylePara elsevierViewall">NPT was positive in all patients with double positivity to SPT and NT; in 6 of 11 patients (54.5%) with positive SPT and negative NT; and in 30 of 36 patients (83.3%) with negative SPT and positive NT. Positivity of NT and NPT was observed in 36 patients (69.6%), while positivity of SPT and NPT was observed in 15 patients (26.8%). This difference was statistically highly significant (p<span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>0.0001).</p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Discussion</span><p id="par0065" class="elsevierStylePara elsevierViewall">IgE antibodies are a key factor in hypersensitivity diseases<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a> and their detection by skin tests or by in vitro measurement reveals atopic sensitisation. When results of these tests are in agreement with history data, and above all when a cause-effect relationship with the exposure to given allergen(s) is apparent, the diagnosis of clinical allergy is achieved. However, it is not rare to observe subjects with rhinitis whose history of suspected allergy is not confirmed by IgE tests (performed with adequate material and optimal technique), and this commonly leads to a diagnosis of non-allergic rhinitis. In patients with seasonal symptoms occurring in correspondence to the presence in the air of known allergens, searching for allergy using other tests is warranted. In recent years, new in vitro tests assessing the cell reactivity to the allergen, such as the basophil activation test, have been introduced.<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a> However, their diagnostic value is still under evaluation.</p><p id="par0070" class="elsevierStylePara elsevierViewall">Another approach to investigate the matter is to find the IgE antibodies directly in the nasal mucosa. The possibility of an exclusively local production of allergen-specific IgE antibodies was first demonstrated in 1975,<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a> subsequently confirmed,<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a> and recently reviewed by Rondon et al. who estimated that a local IgE production occurs in about 40% of the non-allergic rhinitis patients and proposed for such entity the definition of local allergic rhinitis.<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a> Of course, it must be demonstrated that the locally produced IgE are able to elicit symptoms, and this requires nasal symptoms to be reproduced by a NPT using the suspected allergen(s).</p><p id="par0075" class="elsevierStylePara elsevierViewall">We used this approach to evaluate children with rhinitis symptoms during the months when <span class="elsevierStyleItalic">Alternaria</span> spores are present in their living area. Of the 56 children, 20 (37.5%) were positive to SPT, and 45 (80.3%) were positive to NT. We chose to use SPT instead of in vitro IgE measurement because SPT remains the most sensitive test even using the recent in vitro tests with improved performances<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a> The most interesting finding was that 36 subjects (64.3%) had a negative SPT and a positive NT. As expected, the NPT with the <span class="elsevierStyleItalic">Alternaria</span> extract was positive in all patients with double positivity to SPT and NT, but was also positive in 69% of patients with positive NT compared with 27% of those with positive SPT, this being a highly significant difference.</p><p id="par0080" class="elsevierStylePara elsevierViewall">There are reports regarding the role of <span class="elsevierStyleItalic">Alternaria</span> in adult patients with nasal polyposis, as assessed by measurement of specific IgE in tissues homogenates of polyps<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">17</span></a> or sinus tissues,<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">18</span></a> but to the best of our knowledge there are no studies investigating the local production of specific IgE to <span class="elsevierStyleItalic">Alternaria</span> in patients with seasonal rhinitis. However, there is a possible relationship between the findings of our study in children and from the investigations on nasal polyposis in adults. In fact, the persistent exposure to the causative allergen in the absence of a clinical diagnosis and a consequent treatment may lead to rhinosinusal chronic inflammation and to the formation of nasal polyps.</p><p id="par0085" class="elsevierStylePara elsevierViewall">Our finding that sensitisation to <span class="elsevierStyleItalic">Alternaria</span> is frequently expressed by exclusive production of specific IgE in the nasal mucosa suggests the need to perform a measurement of IgE in the nasal mucosa in subjects with seasonal rhinitis and negative SPT during the period of presence of <span class="elsevierStyleItalic">Alternaria</span> spores. The detection of specific IgE in the nose may be able to recognise the real causative agent and to avoid an incorrect diagnosis of non-allergic rhinitis.</p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Conflict of interest</span><p id="par0090" class="elsevierStylePara elsevierViewall">The authors declare they have no conflict of interest.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:8 [ 0 => array:2 [ "identificador" => "xres86094" "titulo" => array:5 [ 0 => "Abstract" 1 => "Background" 2 => "Methods" 3 => "Results" 4 => "Conclusions" ] ] 1 => array:2 [ "identificador" => "xpalclavsec74258" "titulo" => "Keywords" ] 2 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 3 => array:3 [ "identificador" => "sec0010" "titulo" => "Methods" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "sec0015" "titulo" => "Patients" ] 1 => array:2 [ "identificador" => "sec0020" "titulo" => "Nasal IgE test" ] 2 => array:2 [ "identificador" => "sec0025" "titulo" => "Nasal provocation test (NPT)" ] 3 => array:2 [ "identificador" => "sec0030" "titulo" => "Statistical analysis" ] ] ] 4 => array:2 [ "identificador" => "sec0035" "titulo" => "Results" ] 5 => array:2 [ "identificador" => "sec0040" "titulo" => "Discussion" ] 6 => array:2 [ "identificador" => "sec0045" "titulo" => "Conflict of interest" ] 7 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2011-01-21" "fechaAceptado" => "2011-03-03" "PalabrasClave" => array:1 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec74258" "palabras" => array:5 [ 0 => "<span class="elsevierStyleItalic">Alternaria</span>" 1 => "Local production" 2 => "Nasal provocation test" 3 => "Rhinitis" 4 => "Specific IgE" ] ] ] ] "tieneResumen" => true "resumen" => array:1 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "<span class="elsevierStyleSectionTitle">Background</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Rhinitis is a very common disease, frequently caused by sensitisation to inhalant allergens. Negative results from skin prick tests (SPT) and in vitro IgE tests generally lead to a diagnosis of non-allergic rhinitis. However, it is possible, as indicated by studies addressed with dust mites or pollens that the production of specific IgE occurs exclusively at nasal level.</p> <span class="elsevierStyleSectionTitle">Methods</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">We measured specific nasal IgE in children suffering from rhinitis in the periods when <span class="elsevierStyleItalic">Alternaria</span> spores were present in the air.</p><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">All subjects underwent SPT with a standard panel of aeroallergens (Stallergenes, Milan, Italy) and, in the same session, to nasal IgE test (NT). Nasal provocation test (NPT) with <span class="elsevierStyleItalic">Alternaria</span> was used as reference.</p> <span class="elsevierStyleSectionTitle">Results</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Fifty-six subjects were included in the study. Of them, 20 (37.5%) were positive to SPT and 45 (80.3%) were positive to NT. In particular, 11 subjects (19.6%) had a positive SPT and a negative NT; 36 (64.3%) had a negative SPT and a positive NT; and 9 (16.1%) were positive to both tests. Positivity of NT and NPT was observed in 36 patients (69.6%), while positivity of SPT and NPT was observed in 15 patients (26.8%). This difference was highly significant (p<span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>0.0001).</p> <span class="elsevierStyleSectionTitle">Conclusions</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">These findings suggest that sensitisation to <span class="elsevierStyleItalic">Alternaria</span> is frequently expressed by exclusive production of specific IgE in the nasal mucosa. Thus, measuring nasal IgE in children with rhinitis and negative SPT during the period of presence of <span class="elsevierStyleItalic">Alternaria</span> spores seems helpful to avoid a mistaken diagnosis of non-allergic rhinitis.</p>" ] ] "multimedia" => array:1 [ 0 => array:7 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Age (months) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Number \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">SPT + \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">NT + \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">NPT + \t\t\t\t\t\t\n \t\t\t\t</td></tr></thead><tbody title="tbody"><tr title="table-row"><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">Males \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">123.3<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>42.5 \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">26 (46.4%) \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 (14.3%) \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 (39.3%) \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">21 (37.5%) \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 " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Females \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">149.8<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>39.2 \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">30 (53.6%) \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 (21.4%) \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 (41.1%) \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 (42.9%) \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab165443.png" ] ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Results of skin prick test, nasal IgE test, and nasal provocation test.</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:18 [ 0 => array:3 [ "identificador" => "bib0005" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:1 [ "referenciaCompleta" => "Alergologica. 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| 2019 November | 0 | 1 | 1 |
| 2019 October | 0 | 1 | 1 |
| 2019 September | 0 | 2 | 2 |
| 2019 August | 0 | 2 | 2 |
| 2019 July | 0 | 6 | 6 |
| 2019 May | 0 | 21 | 21 |
| 2019 April | 1 | 7 | 8 |
| 2018 January | 1 | 0 | 1 |
| 2017 December | 2 | 2 | 4 |
| 2017 November | 6 | 2 | 8 |
| 2017 October | 6 | 1 | 7 |
| 2017 September | 4 | 8 | 12 |
| 2017 August | 11 | 3 | 14 |
| 2017 July | 12 | 2 | 14 |
| 2017 June | 8 | 4 | 12 |
| 2017 May | 5 | 12 | 17 |
| 2017 April | 5 | 6 | 11 |
| 2017 March | 6 | 12 | 18 |
| 2017 February | 10 | 1 | 11 |
| 2017 January | 1 | 2 | 3 |
| 2016 December | 6 | 4 | 10 |
| 2016 November | 16 | 3 | 19 |
| 2016 October | 24 | 7 | 31 |
| 2016 September | 10 | 4 | 14 |
| 2016 August | 8 | 4 | 12 |
| 2016 July | 8 | 2 | 10 |
| 2016 June | 16 | 6 | 22 |
| 2016 May | 9 | 9 | 18 |
| 2016 April | 17 | 15 | 32 |
| 2016 March | 12 | 8 | 20 |
| 2016 February | 9 | 8 | 17 |
| 2016 January | 8 | 9 | 17 |
| 2015 December | 8 | 8 | 16 |
| 2015 November | 10 | 6 | 16 |
| 2015 October | 21 | 5 | 26 |
| 2015 September | 7 | 4 | 11 |
| 2015 August | 11 | 3 | 14 |
| 2015 July | 5 | 0 | 5 |
| 2015 June | 1 | 3 | 4 |
| 2015 May | 4 | 0 | 4 |
| 2015 April | 13 | 6 | 19 |
| 2015 March | 7 | 3 | 10 |
| 2015 February | 19 | 5 | 24 |
| 2015 January | 24 | 2 | 26 |
| 2014 December | 22 | 6 | 28 |
| 2014 November | 17 | 3 | 20 |
| 2014 October | 17 | 8 | 25 |
| 2014 September | 25 | 4 | 29 |
| 2014 August | 11 | 2 | 13 |
| 2014 July | 17 | 0 | 17 |
| 2014 June | 14 | 1 | 15 |
| 2014 May | 16 | 5 | 21 |
| 2014 April | 4 | 3 | 7 |
| 2014 March | 42 | 12 | 54 |
| 2014 February | 28 | 8 | 36 |
| 2014 January | 31 | 5 | 36 |
| 2013 December | 29 | 6 | 35 |
| 2013 November | 42 | 8 | 50 |
| 2013 October | 30 | 9 | 39 |
| 2013 September | 32 | 4 | 36 |
| 2013 August | 37 | 10 | 47 |
| 2013 July | 33 | 9 | 42 |
| 2013 June | 15 | 3 | 18 |
| 2013 May | 18 | 4 | 22 |
| 2013 April | 15 | 9 | 24 |
| 2013 March | 19 | 5 | 24 |
| 2013 February | 17 | 6 | 23 |
| 2013 January | 9 | 1 | 10 |
| 2012 December | 7 | 3 | 10 |
| 2012 November | 0 | 5 | 5 |
| 2012 October | 1 | 1 | 2 |
| 2012 September | 1 | 1 | 2 |
| 2012 March | 572 | 0 | 572 |
Show all
