Editorial
Novel Biomarkers in Severe Asthma
Nuevos biomarcadores del asma grave
Eleftherios Zervas, Konstantinos Samitas, Mina Gaga
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7th Respiratory Medicine Dept. and Asthma Center, Athens Chest Hospital «Sotiria», Atenas, Greece
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"tienePdf" => "en" "tieneTextoCompleto" => "en" "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "177" "paginaFinal" => "179" ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Fenotipos del asma, ¿son importantes?" ] ] "contieneTextoCompleto" => array:1 [ "en" => true ] "contienePdf" => array:1 [ "en" => true ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1792 "Ancho" => 2700 "Tamanyo" => 390383 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Clinical phenotypes of asthma and treatment. Phenotypes are represented according to the age of onset, severity of the disease, Th2 or non-Th2-dependent inflammation and influence of genetic background. In addition to classical therapy with β agonist, the specific treatments for each group are reported in italic. Ab, antibody; CysLTs, Cysteinyl leukotrienes; TSLP, thymic stromal lymphopoietin; ILC, innate lymphoid cells.</p>" ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "James G. Martin, Alice Panariti" "autores" => array:2 [ 0 => array:2 [ "nombre" => "James G." "apellidos" => "Martin" ] 1 => array:2 [ "nombre" => "Alice" "apellidos" => "Panariti" ] ] ] ] ] "idiomaDefecto" => "en" "Traduccion" => array:1 [ "es" => array:9 [ "pii" => "S0300289616303441" "doi" => "10.1016/j.arbres.2016.11.016" "estado" => "S300" "subdocumento" => "" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:1 [ "total" => 0 ] "idiomaDefecto" => "es" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0300289616303441?idApp=UINPBA00003Z" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S1579212917300101?idApp=UINPBA00003Z" "url" => "/15792129/0000005300000004/v1_201704070039/S1579212917300101/v1_201704070039/en/main.assets" ] "en" => array:12 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Editorial</span>" "titulo" => "Novel Biomarkers in Severe Asthma" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "175" "paginaFinal" => "176" ] ] "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "Eleftherios Zervas, Konstantinos Samitas, Mina Gaga" "autores" => array:3 [ 0 => array:2 [ "nombre" => "Eleftherios" "apellidos" => "Zervas" ] 1 => array:2 [ "nombre" => "Konstantinos" "apellidos" => "Samitas" ] 2 => array:4 [ "nombre" => "Mina" "apellidos" => "Gaga" "email" => array:1 [ 0 => "minagaga@yahoo.com" ] "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">*</span>" "identificador" => "cor0005" ] ] ] ] "afiliaciones" => array:1 [ 0 => array:2 [ "entidad" => "7th Respiratory Medicine Dept. and Asthma Center, Athens Chest Hospital «Sotiria», Atenas, Greece" "identificador" => "aff0005" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Nuevos biomarcadores del asma grave" ] ] "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall">Severe asthma is increasingly associated with many different specific phenotypes and endotypes as well as increased morbidity. Asthma-related healthcare costs are rising, accompanied by a pressing need for effective therapy.<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">1</span></a> Although there are no definitive epidemiologic data on the prevalence of severe asthma, approximately 5%–10% of patients are probably affected by severe asthma, and 1%–2% of these, with significant geographic variations, have severe treatment-resistant/refractory asthma.<a class="elsevierStyleCrossRefs" href="#bib0060"><span class="elsevierStyleSup">1,2</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">The concept of asthma severity has evolved substantially over the years. According to the latest joint ERS/ATS Taskforce, severe asthma is defined as asthma that requires treatment with high-dose inhaled corticosteroids (ICS) plus a second controller (and/or systemic corticosteroids) to prevent it from becoming uncontrolled, or that remains uncontrolled despite this therapy.<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">2</span></a> It is, however, increasingly recognized that severe asthma is not a single disease, as evidenced by the variety of clinical presentations, pathophysiological characteristics and outcomes. Studies of severe asthma cohorts, such as the ENFUMOSA/BIOAIR studies, the TENOR/SARP studies, the Belgium Severe Asthma study and, more recently, the U-BIOPRED study, also show that severe asthma is an extremely heterogeneous disease in terms of clinical presentation and pathophysiologic mechanisms. Asthma is usually characterized as a T2-high disease, associated with atopy and/or eosinophilic airway inflammation. However, inflammation in severe asthma is not necessarily characterized by eosinophilia and Th2 type cytokines, but may in many cases be T2-low, either neutrophilic or pauci-granulocytic.<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">3</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">The T2-high asthmatic endotypes are associated with increased epithelial expression of Th2 cytokines, such as interleukin (IL)-4, IL-5, and IL-13. Although heterogeneous in nature, the designation of the Th2-high endotype has primarily been based on the presence of eosinophilic airway inflammation, with sputum and/or blood eosinophils used as relevant biomarkers.<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">4</span></a> Other well studied and established biomarkers for T2-high asthma are exhaled NO, total IgE and serum periostin. In a recent study by Busse et al., the cut points used to define a high level of T2 immune activation were IgE ≥100<span class="elsevierStyleHsp" style=""></span>IU/mL, eosinophil count ≥300/mL and <span class="elsevierStyleItalic">F</span><span class="elsevierStyleInf">ENO</span> ≥30 parts per billion.<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">5</span></a> Total IgE and blood eosinophils are currently biomarkers of disease and also key-elements in the management algorithm for a specific subgroup of severe asthmatics eligible for anti-IgE (omalizumab), anti-IL-5 (mepolizumab) and anti-IL-4Ra (dupilumab) treatment. Moreover, periostin-high severe asthmatics have been found to be more responsive to anti-IL-13 treatment with lebrikizumab. The usefulness of combining biomarkers for T2-high severe asthmatic disease was also shown in a study by Hanania et al., which demonstrated that severe atopic asthmatics with high IgE levels and high T2 markers, i.e., elevated blood eosinophils, FeNO, and periostin, were better responders when treated with omalizumab.<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">6</span></a> Novel research on T2-high biomarkers also includes angiopoietins-1, osteopontin, GM-CSF and IL-13.</p><p id="par0020" class="elsevierStylePara elsevierViewall">T2-low disease was initially considered to be a rather rare entity in the context of severe asthma. However, recent data indicate that it may affect up to one third of severe asthmatics.<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">7</span></a> Although T2-high asthma with atopy and/or eosinophilia is easy to distinguish, there is no widely-accepted definition of T2-low disease. In most cases, the T2-low endotype is defined by the absence of markers of Th2-mediated inflammation, and is usually characterized by neutrophilic or, less commonly, pauci-granulocytic infiltration in the airways. However, there is no consensus regarding the percentage of sputum neutrophils required to define the neutrophilic asthma phenotype, and different cut-off values, ranging from 40% to 76%, have been used in the literature.<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">3</span></a> Besides sputum differential cell counts, other specific biomarkers to discriminate T2-low from T2-high asthma are under investigation, but are not yet used in clinical practice.<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">8</span></a> IL-8, a cytokine related to neutrophilic chemotaxis and degranulation, is elevated in the sputum of patients with treatment-resistant severe asthma, and is associated with airway colonization with potentially pathogenic micro-organisms and neutrophilic airway inflammation.<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">9</span></a> Moreover, receptors for IL-8, such as CXCR1 and CXCR2, are increased in the sputum of patients with neutrophilic asthma. Myeloperoxidase (MPO) and neutrophil elastase (NE) are 2 other biomarkers under investigation for neutrophilic asthma, mainly assessed in the sputum of severe asthmatics.<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">10</span></a> TNF-α started as a promising biomarker and target for treatment in neutrophilic severe asthma, however initial clinical studies were rather disappointing. Recently, IL-17, a biomarker of Th17 pathway activation leading to non-type 2 inflammation, has also been the subject of evaluation as a biomarker and a strong correlation between IL-17 and both IL-8 and neutrophils has been proven in induced sputum and blood of severe asthmatics.<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">11</span></a> All possible biomarkers discussed above concern neutrophilic T2-low asthmatic endotype; in the subgroup of patients with pauci-granulocytic asthma there is a lack of characteristic biomarkers. As this patient population lacks a predominant inflammatory type, it is possible that other markers of cardinal features of severe asthma, such as airway remodelling (i.e., osteopontin or angiopoetins), may serve as relevant biomarkers.</p><p id="par0025" class="elsevierStylePara elsevierViewall">In conclusion, current strategies in the management of severe asthma involve the use of biomarkers in phenotyping and the treatment decision-making process. We currently have a number of well-studied and established biomarkers for T2-high severe asthma, however there is a clear need for biomarkers in severe T2-low disease. Currently, the most logical approach to identify T2-low asthma in everyday clinical practice is to consider the absence of markers of atopic and/or eosinophilic asthma. Understanding the pathogenetic mechanisms behind the T2-low endotype is a necessary step in identifying future biomarkers.</p></span>" "pdfFichero" => "main.pdf" "tienePdf" => true "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as: Zervas E, Samitas K, Gaga M. Nuevos biomarcadores del asma grave. Arch Bronconeumol. 2017;53:175–176.</p>" ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:11 [ 0 => array:3 [ "identificador" => "bib0060" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Severe asthma in adults: an orphan disease?" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "M. Gaga" 1 => "E. Zervas" 2 => "K. Samitas" 3 => "E.H. Bel" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.ccm.2012.06.008" "Revista" => array:6 [ "tituloSerie" => "Clin Chest Med" "fecha" => "2012" "volumen" => "33" "paginaInicial" => "571" "paginaFinal" => "583" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/22929103" "web" => "Medline" ] ] ] ] ] ] ] ] 1 => array:3 [ "identificador" => "bib0065" "etiqueta" => "2" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "K.F. Chung" 1 => "S.E. Wenzel" 2 => "J.L. Brozek" 3 => "A. Bush" 4 => "M. Castro" 5 => "P.J. Sterk" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1183/09031936.00202013" "Revista" => array:6 [ "tituloSerie" => "Eur Respir J" "fecha" => "2014" "volumen" => "43" "paginaInicial" => "343" "paginaFinal" => "373" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/24337046" "web" => "Medline" ] ] ] ] ] ] ] ] 2 => array:3 [ "identificador" => "bib0070" "etiqueta" => "3" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "T2-low asthma: current approach to diagnosis and therapy" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "K. Samitas" 1 => "E. Zervas" 2 => "M. Gaga" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1097/MCP.0000000000000342" "Revista" => array:6 [ "tituloSerie" => "Curr Opin Pulm Med" "fecha" => "2017" "volumen" => "23" "paginaInicial" => "48" "paginaFinal" => "55" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/27798418" "web" => "Medline" ] ] ] ] ] ] ] ] 3 => array:3 [ "identificador" => "bib0075" "etiqueta" => "4" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Severe eosinophilic asthma treated with mepolizumab stratified by baseline eosinophil thresholds: a secondary analysis of the DREAM and MENSA studies" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "H.G. Ortega" 1 => "S.W. Yancey" 2 => "B. Mayer" 3 => "N.B. Gunsoy" 4 => "O.N. Keene" 5 => "E.R. Bleecker" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/S2213-2600(16)30031-5" "Revista" => array:6 [ "tituloSerie" => "Lancet Respir Med" "fecha" => "2016" "volumen" => "4" "paginaInicial" => "549" "paginaFinal" => "556" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/27177493" "web" => "Medline" ] ] ] ] ] ] ] ] 4 => array:3 [ "identificador" => "bib0080" "etiqueta" => "5" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Biomarker profiles in asthma with high vs low airway reversibility and poor disease control" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "W.W. Busse" 1 => "S.T. Holgate" 2 => "S.W. Wenzel" 3 => "P. Klekotka" 4 => "Y. Chon" 5 => "J. Feng" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1378/chest.14-2457" "Revista" => array:6 [ "tituloSerie" => "Chest" "fecha" => "2015" "volumen" => "148" "paginaInicial" => "1489" "paginaFinal" => "1496" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/26226215" "web" => "Medline" ] ] ] ] ] ] ] ] 5 => array:3 [ "identificador" => "bib0085" "etiqueta" => "6" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Exploring the effects of omalizumab in allergic asthma: an analysis of biomarkers in the EXTRA study" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "N.A. Hanania" 1 => "S. Wenzel" 2 => "K. Rosen" 3 => "H.J. Hsieh" 4 => "S. Mosesova" 5 => "D.F. Choy" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1164/rccm.201208-1414OC" "Revista" => array:6 [ "tituloSerie" => "Am J Respir Crit Care Med" "fecha" => "2013" "volumen" => "187" "paginaInicial" => "804" "paginaFinal" => "811" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/23471469" "web" => "Medline" ] ] ] ] ] ] ] ] 6 => array:3 [ "identificador" => "bib0090" "etiqueta" => "7" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Heterogeneity of phenotypes in severe asthmatics. The Belgian Severe Asthma Registry (BSAR)" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "F. Schleich" 1 => "G. Brusselle" 2 => "R. Louis" 3 => "O. Vandenplas" 4 => "A. Michils" 5 => "C. Pilette" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.rmed.2014.10.007" "Revista" => array:6 [ "tituloSerie" => "Respir Med" "fecha" => "2014" "volumen" => "108" "paginaInicial" => "1723" "paginaFinal" => "1732" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/25456708" "web" => "Medline" ] ] ] ] ] ] ] ] 7 => array:3 [ "identificador" => "bib0095" "etiqueta" => "8" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Biomarkers in the management of difficult asthma" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "F. Schleich" 1 => "D. Sophie" 2 => "L. Renaud" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Curr Top Med Chem" "fecha" => "2016" "volumen" => "16" "paginaInicial" => "1561" "paginaFinal" => "1573" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/26467509" "web" => "Medline" ] ] ] ] ] ] ] ] 8 => array:3 [ "identificador" => "bib0100" "etiqueta" => "9" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Potentially pathogenic airway bacteria and neutrophilic inflammation in treatment resistant severe asthma" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "B.J. Green" 1 => "S. Wiriyachaiporn" 2 => "C. Grainge" 3 => "G.B. Rogers" 4 => "V. Kehagia" 5 => "L. Lau" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1371/journal.pone.0100645" "Revista" => array:5 [ "tituloSerie" => "PLOS ONE" "fecha" => "2014" "volumen" => "9" "paginaInicial" => "e100645" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/24955983" "web" => "Medline" ] ] ] ] ] ] ] ] 9 => array:3 [ "identificador" => "bib0105" "etiqueta" => "10" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "The neutrophilic inflammatory phenotype is associated with systemic inflammation in asthma" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "L.G. Wood" 1 => "K.J. Baines" 2 => "J. Fu" 3 => "H.A. Scott" 4 => "P.G. Gibson" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1378/chest.11-1838" "Revista" => array:6 [ "tituloSerie" => "Chest" "fecha" => "2012" "volumen" => "142" "paginaInicial" => "86" "paginaFinal" => "93" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/22345378" "web" => "Medline" ] ] ] ] ] ] ] ] 10 => array:3 [ "identificador" => "bib0110" "etiqueta" => "11" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Increased serum IL-17 is an independent risk factor for severe asthma" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "I. Agache" 1 => "C. Ciobanu" 2 => "C. Agache" 3 => "M. Anghel" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.rmed.2010.02.018" "Revista" => array:6 [ "tituloSerie" => "Respir Med" "fecha" => "2010" "volumen" => "104" "paginaInicial" => "1131" "paginaFinal" => "1137" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/20338742" "web" => "Medline" ] ] ] ] ] ] ] ] ] ] ] ] ] "idiomaDefecto" => "en" "url" => "/15792129/0000005300000004/v1_201704070039/S1579212917300186/v1_201704070039/en/main.assets" "Apartado" => array:4 [ "identificador" => "46447" "tipo" => "SECCION" "en" => array:2 [ "titulo" => "Editorial" "idiomaDefecto" => true ] "idiomaDefecto" => "en" ] "PDF" => "https://static.elsevier.es/multimedia/15792129/0000005300000004/v1_201704070039/S1579212917300186/v1_201704070039/en/main.pdf?idApp=UINPBA00003Z&text.app=https://archbronconeumol.org/" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S1579212917300186?idApp=UINPBA00003Z" ]
| Year/Month | Html | Total | |
|---|---|---|---|
| 2024 November | 4 | 2 | 6 |
| 2024 October | 56 | 28 | 84 |
| 2024 September | 49 | 36 | 85 |
| 2024 August | 86 | 44 | 130 |
| 2024 July | 54 | 32 | 86 |
| 2024 June | 82 | 43 | 125 |
| 2024 May | 72 | 31 | 103 |
| 2024 April | 52 | 38 | 90 |
| 2024 March | 35 | 24 | 59 |
| 2024 February | 27 | 24 | 51 |
| 2023 March | 10 | 5 | 15 |
| 2023 February | 79 | 17 | 96 |
| 2023 January | 36 | 42 | 78 |
| 2022 December | 67 | 34 | 101 |
| 2022 November | 85 | 30 | 115 |
| 2022 October | 94 | 34 | 128 |
| 2022 September | 75 | 23 | 98 |
| 2022 August | 71 | 44 | 115 |
| 2022 July | 58 | 33 | 91 |
| 2022 June | 41 | 37 | 78 |
| 2022 May | 57 | 30 | 87 |
| 2022 April | 48 | 30 | 78 |
| 2022 March | 63 | 50 | 113 |
| 2022 February | 70 | 31 | 101 |
| 2022 January | 69 | 44 | 113 |
| 2021 December | 62 | 53 | 115 |
| 2021 November | 54 | 42 | 96 |
| 2021 October | 83 | 88 | 171 |
| 2021 September | 36 | 52 | 88 |
| 2021 August | 34 | 39 | 73 |
| 2021 July | 29 | 38 | 67 |
| 2021 June | 48 | 40 | 88 |
| 2021 May | 74 | 55 | 129 |
| 2021 April | 101 | 83 | 184 |
| 2021 March | 81 | 49 | 130 |
| 2021 February | 54 | 30 | 84 |
| 2021 January | 37 | 23 | 60 |
| 2020 December | 43 | 21 | 64 |
| 2020 November | 44 | 25 | 69 |
| 2020 October | 41 | 22 | 63 |
| 2020 September | 36 | 19 | 55 |
| 2020 August | 31 | 23 | 54 |
| 2020 July | 35 | 20 | 55 |
| 2020 June | 25 | 16 | 41 |
| 2020 May | 45 | 16 | 61 |
| 2020 April | 36 | 25 | 61 |
| 2020 March | 34 | 23 | 57 |
| 2020 February | 36 | 23 | 59 |
| 2020 January | 56 | 20 | 76 |
| 2019 December | 45 | 32 | 77 |
| 2019 November | 35 | 35 | 70 |
| 2019 October | 52 | 25 | 77 |
| 2019 September | 56 | 27 | 83 |
| 2019 August | 37 | 31 | 68 |
| 2019 July | 29 | 24 | 53 |
| 2019 June | 16 | 26 | 42 |
| 2019 May | 26 | 40 | 66 |
| 2019 April | 34 | 67 | 101 |
| 2019 March | 34 | 41 | 75 |
| 2019 February | 37 | 30 | 67 |
| 2019 January | 33 | 31 | 64 |
| 2018 December | 27 | 22 | 49 |
| 2018 November | 78 | 31 | 109 |
| 2018 October | 104 | 26 | 130 |
| 2018 September | 37 | 11 | 48 |
| 2018 May | 30 | 0 | 30 |
| 2018 April | 32 | 11 | 43 |
| 2018 March | 61 | 8 | 69 |
| 2018 February | 58 | 10 | 68 |
| 2018 January | 188 | 16 | 204 |
| 2017 December | 174 | 21 | 195 |
| 2017 November | 32 | 7 | 39 |
| 2017 October | 11 | 10 | 21 |
| 2017 September | 21 | 10 | 31 |
| 2017 August | 20 | 16 | 36 |
| 2017 July | 24 | 15 | 39 |
| 2017 June | 0 | 1 | 1 |
| 2017 May | 0 | 1 | 1 |
| 2017 April | 1 | 0 | 1 |
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