Case report
Chronic granulomatous disease associated with common variable immunodeficiency – 2 clinical cases
Doença granulomatosa crónica associada com a imunodeficiência comum variável - 2 casos clínicos
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Pacheco, A. Morais, R. Rolo, L. Ferreira, R. Nabiço, J. Cunha" "autores" => array:6 [ 0 => array:4 [ "nombre" => "C." "apellidos" => "Pacheco" "email" => array:1 [ 0 => "ceciliafpacheco@gmail.com" ] "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" => "A." "apellidos" => "Morais" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0010" ] ] ] 2 => array:3 [ "nombre" => "R." "apellidos" => "Rolo" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] ] ] 3 => array:3 [ "nombre" => "L." 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"apellidos" => "Cunha" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] ] ] ] "afiliaciones" => array:3 [ 0 => array:3 [ "entidad" => "Serviço de Pneumologia, Hospital de Braga, Braga, Portugal" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Serviço de Pneumologia, Centro Hospitalar de São João; Faculdade de Medicina da Universidade do Porto, Porto, Portugal" "etiqueta" => "b" "identificador" => "aff0010" ] 2 => array:3 [ "entidad" => "Serviço de Medicina Interna, Hospital de Braga, Braga, Portugal" "etiqueta" => "c" "identificador" => "aff0015" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "pt" => array:1 [ "titulo" => "Doença granulomatosa crónica associada com a imunodeficiência comum variável - 2 casos clínicos" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1 and 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1v2.jpeg" "Alto" => 507 "Ancho" => 1800 "Tamanyo" => 99682 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Thoracic CT scan from patient 1, November 2009, showing diffuse peribronchovascular micronodules detected in lung parenchyma.</p>" ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Common variable immunodeficiency (CVID) is a rare primary immunodeficiency syndrome characterized by impaired B-cell differentiation with inaccurate immunoglobulin production.<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> It is defined by markedly reduced serum concentrations of IgG, combined with low levels of IgA and/or IgM, poor or absent response to immunizations in a patient without any other signs of immunodeficiency. The prevalence in Europe is estimated to be around 1:50,000–1:200,000.<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> The etiology is still unknown, but it appears to result from a variety of gene defects (e.g., ICOS, TACI, BAFF-R, CD19, CD20, CD21, and CD81), most of which are sporadic rather than familiar.<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2–4</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">Although rare, systemic granulomatous disease related to CVID is well documented (>50 case reports). Granulomatous non-caseous lesions can be detected in the lung, liver, spleen, gastrointestinal tract, lymph nodes, skin and eye in almost 10% of the patients with CVID.<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2,5</span></a> Some of them also show clinical manifestations similar to sarcoidosis, with symptoms like dyspnea, persistent cough, asthenia, anorexia and arthralgia.<a class="elsevierStyleCrossRefs" href="#bib0030"><span class="elsevierStyleSup">6,7</span></a> Granulomatous lesions in CVID may not only affect the same organs as sarcoidosis but also be histologically indistinguishable.<a class="elsevierStyleCrossRefs" href="#bib0040"><span class="elsevierStyleSup">8–11</span></a> As a consequence, sarcoidosis is often incorrectly diagnosed in GD-CVID patients, with GD-CVID considered as a distinguished entity.<a class="elsevierStyleCrossRefs" href="#bib0060"><span class="elsevierStyleSup">12–15</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">The authors present two clinical cases of CVID with systemic involvement by non- caseous granulomas.</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Clinical cases</span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">1st case</span><p id="par0020" class="elsevierStylePara elsevierViewall">A 39-year-old male, mechanic engineer, non-smoker, had been diagnosed with CVID 4 years ago, under treatment with intravenous IgG. He had previously had several respiratory infections since childhood. In November 2009, after a routine chest X-ray with mediastinum enlargement, a thoracic CT scan was performed and numerous adenopathies in the prevascular, pretracheal as well as in the right pulmonary hilum were observed. Additionally, diffuse peribronchovascular micronodules were detected in lung parenchyma (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1 and 2</a>). The patient had no relevant clinical complaints or alterations at physical examination. Besides hypogammaglobulinemia (IgG 287<span class="elsevierStyleHsp" style=""></span>mg/dL; IgM 8<span class="elsevierStyleHsp" style=""></span>mg/dL; IgA 6<span class="elsevierStyleHsp" style=""></span>mg/dL) and slight thrombocytopenia (platelets 127<span class="elsevierStyleHsp" style=""></span>×<span class="elsevierStyleHsp" style=""></span>10<span class="elsevierStyleSup">3</span><span class="elsevierStyleHsp" style=""></span>μL), no other serum related alterations were noticed. Lung function tests revealed a mild obstructive pattern. A bronchoscopy with bronchoalveolar lavage (BAL) was performed. It showed lymphocytic alveolitis (28%) with a slight increase in CD4/CD8 ratio (2.2), and no microorganism was isolated or malignant cell detected. A bone marrow biopsy was also performed, which showed non-caseous granulomas. There were no clinical or imagiological indications of other organ involvement. At this stage, the patient was started on oral corticotherapy which led to progressive clinical and radiological improvement ending in total disease resolution which continued after the patient come off medication.</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">2nd case</span><p id="par0025" class="elsevierStylePara elsevierViewall">A 38-year-old male nurse, a non-smoker, had been diagnosed with CVID a year earlier, treated with intravenous IgG. Previously, he had had several respiratory infections since childhood. In February 2010, he began to suffer from asthenia, anorexia, and erythema nodosum. A thoracic CT scan showed mediastinal and bilateral symmetrical hilar adenopathies. Lung function tests were normal. Bronchoscopy with BAL revealed lymphocytosis (35%) with a slight increase in CD4/CD8 ratio (2.6) and no microorganism or malignant cells were detected. Endobronchial ultrasound biopsy showed non-necrotizing granulomatous infiltration. There were no signs of extrathoracic involvement. After diagnosis, he was prescribed symptomatic therapy only (antitussives and anti-inflammatories). After 6 months, there was a spontaneous resolution of the disease, that is to say, the patient became asymptomatic and no imagiologic alterations or signs of recurrence have been detected so far.</p></span></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Discussion</span><p id="par0030" class="elsevierStylePara elsevierViewall">CVID is a heterogeneous disease, characterized by recurrent infections, particularly bacterial infections often occurring in the respiratory or gastrointestinal tract, autoimmunity phenomena, predisposition to malignant diseases, and granulomatous inflammation (GD-CVID).<a class="elsevierStyleCrossRefs" href="#bib0025"><span class="elsevierStyleSup">5,16–18</span></a> Although GD-CVID is well documented, the etiology is still unknown and treatment undefined.<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">18</span></a></p><p id="par0035" class="elsevierStylePara elsevierViewall">The link between CVID and the granulomatous disease seems logical according to the immunological mechanisms that are implied in the CVID pathophysiology. However, the absence of granulomatous disease in other immunodeficiencies (as hypogammaglobulinemia related to X) suggests that GD-CVID is not caused by recurrent/persistent infections.<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a> A recent hypothesis is that high levels of tumor necrosis factor (TNF) might be related to the development of granulomas in these patients.<a class="elsevierStyleCrossRefs" href="#bib0030"><span class="elsevierStyleSup">6,12</span></a></p><p id="par0040" class="elsevierStylePara elsevierViewall">Non-caseous granulomatous lesions that affect CVID patients are histologically indistinguishable from those of sarcoidosis. The patient's age and sex, diminished cellular immunity, the systemic involvement, and high levels of angiotensin-converting enzyme are common features for the two pathologies, so a previous story of recurrent/persistent bacterial infections should raise suspicion of CVID.<a class="elsevierStyleCrossRefs" href="#bib0030"><span class="elsevierStyleSup">6,7</span></a> However, in a case–control study comparing GD-CVID patients and patients with pulmonary sarcoidosis, certain differences were detected, such as a random versus perilymphatic micronodular distribution on lung CT scan in GD-CVID patients, besides the higher frequency of consolidations with air bronchogram, bronchiectasis, or halo signs. Biological data showed that BAL CD4/CD8 ratio was significantly lower in GD-CVID. There is a general agreement that the presence of lung involvement is associated with a bad prognosis in CVID, including when a GD-CVID occurs. However Bouvry et al. in their case–control study did not find GD to be a critical determinant of prognosis but found a worse outcome to be linked to the classical complications of CVID such as lymphoma, infection or obstructive lung disease secondary to bronchiectasis.<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a></p><p id="par0045" class="elsevierStylePara elsevierViewall">The clinical presentations of the two reported clinical cases, asymptomatic mediastinal and hilar adenopathies and erythema nodosum, are among the most frequent presentations of sarcoidosis. In addition CVID was already known in both patients; however GD-CVID can, although rarely, be the presentation of the disease. The random distribution of the lung micronodules in the first patient and the slight BAL CD4/CD8 increase are in line with previous reports. However, the therapeutic strategy toward this granulomatous disease has diverged. Although corticotherapy is not universally accepted as a mandatory treatment,<a class="elsevierStyleCrossRefs" href="#bib0060"><span class="elsevierStyleSup">12,15</span></a> it was prescribed for the first patient because of the systemic involvement, namely, the cytopenia secondary to the bone marrow involvement. The second patient did not receive any therapy directed at the GD. However, both of them improved in clinical, analytical, and radiological terms, which is in line with the favorable evolution reported by Bouvry et al.<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> The appropriate treatment for GD-CVID patients has not yet been established.<a class="elsevierStyleCrossRefs" href="#bib0030"><span class="elsevierStyleSup">6,7,12,15</span></a></p><p id="par0050" class="elsevierStylePara elsevierViewall">There are no protocols regarding diagnosis, treatment and follow-up, nor prognosis for GD-CVID patients. Many of these patients are followed individually and in a non-standardized way. All clinicians should be familiar with this pathology because so many organs and systems can be affected.<a class="elsevierStyleCrossRefs" href="#bib0035"><span class="elsevierStyleSup">7,8,17</span></a></p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Ethical disclosures</span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Protection of human and animal subjects</span><p id="par0055" class="elsevierStylePara elsevierViewall">The authors declare that no experiments were performed on humans or animals for this study.</p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Confidentiality of data</span><p id="par0060" class="elsevierStylePara elsevierViewall">The authors declare that they have followed the protocols of their work center on the publication of patient data and that all the patients included in the study received sufficient information and gave their written informed consent to participate in the study.</p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Right to privacy and informed consent</span><p id="par0065" class="elsevierStylePara elsevierViewall">The authors have obtained the written informed consent of the patients or subjects mentioned in the article. The corresponding author is in possession of this document.</p></span></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Conflicts of interest</span><p id="par0070" class="elsevierStylePara elsevierViewall">The authors have no conflicts of interest to declare.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:10 [ 0 => array:3 [ "identificador" => "xres549699" "titulo" => "Abstract" "secciones" => array:3 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Introduction" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Clinical cases" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Conclusion" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec567296" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres549700" "titulo" => "Resumo" "secciones" => array:3 [ 0 => array:2 [ "identificador" => "abst0020" "titulo" => "Introdução" ] 1 => array:2 [ "identificador" => "abst0025" "titulo" => "Casos clínicos" ] 2 => array:2 [ "identificador" => "abst0030" "titulo" => "Conclusão" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec567295" "titulo" => "Palavras-chave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:3 [ "identificador" => "sec0010" "titulo" => "Clinical cases" "secciones" => array:2 [ 0 => array:2 [ "identificador" => "sec0015" "titulo" => "1st case" ] 1 => array:2 [ "identificador" => "sec0020" "titulo" => "2nd case" ] ] ] 6 => array:2 [ "identificador" => "sec0025" "titulo" => "Discussion" ] 7 => array:3 [ "identificador" => "sec0030" "titulo" => "Ethical disclosures" "secciones" => array:3 [ 0 => array:2 [ "identificador" => "sec0035" "titulo" => "Protection of human and animal subjects" ] 1 => array:2 [ "identificador" => "sec0040" "titulo" => "Confidentiality of data" ] 2 => array:2 [ "identificador" => "sec0045" "titulo" => "Right to privacy and informed consent" ] ] ] 8 => array:2 [ "identificador" => "sec0050" "titulo" => "Conflicts of interest" ] 9 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2013-05-13" "fechaAceptado" => "2013-09-09" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec567296" "palabras" => array:4 [ 0 => "Common variable immunodeficiency" 1 => "Granulomas" 2 => "Sarcoidosis" 3 => "Granulomatous disease" ] ] ] "pt" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palavras-chave" "identificador" => "xpalclavsec567295" "palabras" => array:4 [ 0 => "Imunodeficiência comum variável" 1 => "Granulomas" 2 => "Sarcoidose" 3 => "Doença granulomatosa" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:3 [ "titulo" => "Abstract" "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Introduction</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Chronic granulomatous disease associated with common variable immunodeficiency (GD-CVID), although well documented, is rare. Granulomatous lesions can affect several organs and are histologically indistinguishable from sarcoidosis.</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Clinical cases</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Case 1: A 39-year-old male patient with CVID, asymptomatic although with thrombocytopenia and mediastinal-hilar adenopathies. GD-CVID was diagnosed by bone marrow biopsy. Progressive clinical and radiological improvement was obtained with corticotherapy.</p><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Case 2: A 38-year-old male patient with CVID, suffered from asthenia, anorexia, myalgia, lower limbs edemas, and dry cough. He had mediastinal and bilateral hilar adenopathies within which biopsy revealed non-necrotizing granulomatous infiltrate. A spontaneous resolution was detected after 9 months of evolution.</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Conclusion</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">GD-CVID is rare and can mimetize other pathologies, namely, sarcoidosis; it should therefore be publicized and discussed so that it becomes a general clinical knowledge.</p></span>" "secciones" => array:3 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Introduction" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Clinical cases" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Conclusion" ] ] ] "pt" => array:3 [ "titulo" => "Resumo" "resumen" => "<span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Introdução</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">A doença granulomatosa crónica associada à imunodeficiência comum variável (DG-IDCV), apesar de bem documentada, é rara. As lesões granulomatosas podem afectar vários orgãos e são histologicamente indistinguíveis daquelas que caracterizam a sarcoidose.</p></span> <span id="abst0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Casos clínicos</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Caso 1: Doente do sexo masculino, 39 anos, com diagnóstico de imunodeficiência comum variável, clinicamente assintomático, com trombocitopenia e adenopatias pré-traqueais e hilares de novo. O diagnóstico de DG-IDCV foi obtido por biópsia de medula óssea. Iniciou tratamento com corticoterapia com melhoria clínica e radiológica progressiva.</p><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Caso 2: Doente do sexo masculino, 38 anos, com diagnóstico de imunodeficiência comum variável, com queixas de astenia, anorexia, mialgias, edemas dos membros inferiores e tosse seca. Adenopatias mediastínicas e hilares bilaterais cuja biopsia revelou infiltrado granulomatoso não necrotizante. Observou-se uma resolução espontânea após nove meses de evolução.</p></span> <span id="abst0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Conclusão</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">A doença granulomatosa crónica associada a imunodeficiência comum variável é rara. Dado que esta entidade pode mimetizar outras patologias, nomeadamente a sarcoidose, os casos clínicos que se referem à mesma devem ser publicados e discutidos para conhecimento clínico geral.</p></span>" "secciones" => array:3 [ 0 => array:2 [ "identificador" => "abst0020" "titulo" => "Introdução" ] 1 => array:2 [ "identificador" => "abst0025" "titulo" => "Casos clínicos" ] 2 => array:2 [ "identificador" => "abst0030" "titulo" => "Conclusão" ] ] ] ] "multimedia" => array:1 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1 and 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1v2.jpeg" "Alto" => 507 "Ancho" => 1800 "Tamanyo" => 99682 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Thoracic CT scan from patient 1, November 2009, showing diffuse peribronchovascular micronodules detected in lung parenchyma.</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:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Granulomatosis-associated common variable immunodeficiency disorder: a case–control study versus sarcoidosis" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:5 [ 0 => "D. 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| 2022 September | 45 | 26 | 71 |
| 2022 August | 52 | 35 | 87 |
| 2022 July | 58 | 51 | 109 |
| 2022 June | 66 | 29 | 95 |
| 2022 May | 59 | 43 | 102 |
| 2022 April | 90 | 29 | 119 |
| 2022 March | 104 | 40 | 144 |
| 2022 February | 91 | 34 | 125 |
| 2022 January | 84 | 31 | 115 |
| 2021 December | 39 | 46 | 85 |
| 2021 November | 73 | 36 | 109 |
| 2021 October | 56 | 36 | 92 |
| 2021 September | 63 | 33 | 96 |
| 2021 August | 52 | 23 | 75 |
| 2021 July | 37 | 25 | 62 |
| 2021 June | 44 | 30 | 74 |
| 2021 May | 83 | 38 | 121 |
| 2021 April | 159 | 73 | 232 |
| 2021 March | 118 | 36 | 154 |
| 2021 February | 111 | 17 | 128 |
| 2021 January | 72 | 11 | 83 |
| 2020 December | 83 | 9 | 92 |
| 2020 November | 77 | 18 | 95 |
| 2020 October | 47 | 26 | 73 |
| 2020 September | 94 | 24 | 118 |
| 2020 August | 87 | 24 | 111 |
| 2020 July | 108 | 20 | 128 |
| 2020 June | 102 | 26 | 128 |
| 2020 May | 116 | 24 | 140 |
| 2020 April | 99 | 16 | 115 |
| 2020 March | 105 | 22 | 127 |
| 2020 February | 100 | 40 | 140 |
| 2020 January | 98 | 19 | 117 |
| 2019 December | 101 | 20 | 121 |
| 2019 November | 82 | 14 | 96 |
| 2019 October | 803 | 22 | 825 |
| 2019 September | 121 | 22 | 143 |
| 2019 August | 184 | 22 | 206 |
| 2019 July | 224 | 24 | 248 |
| 2019 June | 202 | 18 | 220 |
| 2019 May | 235 | 18 | 253 |
| 2019 April | 220 | 32 | 252 |
| 2019 March | 229 | 15 | 244 |
| 2019 February | 219 | 18 | 237 |
| 2019 January | 229 | 37 | 266 |
| 2018 December | 161 | 9 | 170 |
| 2018 November | 42 | 0 | 42 |
| 2018 October | 70 | 9 | 79 |
| 2018 September | 49 | 5 | 54 |
| 2018 August | 55 | 24 | 79 |
| 2018 July | 49 | 21 | 70 |
| 2018 June | 69 | 18 | 87 |
| 2018 May | 53 | 18 | 71 |
| 2018 April | 100 | 24 | 124 |
| 2018 March | 77 | 19 | 96 |
| 2018 February | 32 | 13 | 45 |
| 2018 January | 30 | 13 | 43 |
| 2017 December | 33 | 19 | 52 |
| 2017 November | 47 | 14 | 61 |
| 2017 October | 41 | 23 | 64 |
| 2017 September | 46 | 19 | 65 |
| 2017 August | 49 | 22 | 71 |
| 2017 July | 30 | 16 | 46 |
| 2017 June | 30 | 16 | 46 |
| 2017 May | 39 | 14 | 53 |
| 2017 April | 7 | 0 | 7 |
| 2017 March | 17 | 7 | 24 |
| 2017 February | 15 | 7 | 22 |
| 2017 January | 22 | 8 | 30 |
| 2016 December | 17 | 11 | 28 |
| 2016 November | 8 | 3 | 11 |
| 2016 October | 13 | 2 | 15 |
| 2016 September | 2 | 2 | 4 |
| 2016 August | 20 | 5 | 25 |
| 2016 July | 4 | 8 | 12 |
| 2016 June | 0 | 2 | 2 |
| 2016 May | 0 | 4 | 4 |
| 2016 April | 32 | 3 | 35 |
| 2016 March | 49 | 6 | 55 |
| 2016 February | 65 | 14 | 79 |
| 2016 January | 29 | 15 | 44 |
| 2015 December | 39 | 10 | 49 |
| 2015 November | 42 | 6 | 48 |
| 2015 October | 40 | 8 | 48 |
| 2015 September | 41 | 10 | 51 |
| 2015 August | 50 | 12 | 62 |
| 2015 July | 43 | 5 | 48 |
| 2015 June | 29 | 6 | 35 |
| 2015 May | 51 | 6 | 57 |
| 2015 April | 42 | 13 | 55 |
| 2015 March | 50 | 3 | 53 |
| 2015 February | 41 | 11 | 52 |
| 2015 January | 66 | 15 | 81 |
| 2014 December | 69 | 13 | 82 |
| 2014 November | 54 | 11 | 65 |
| 2014 October | 95 | 21 | 116 |
| 2014 September | 51 | 28 | 79 |
| 2014 August | 74 | 54 | 128 |
| 2014 July | 95 | 60 | 155 |
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