Scientific Letter
Atypical hemolytic uremic syndrome in intensive care: Case report in an adult
Síndrome hemolítico urémico atípico en cuidados intensivos: caso clínico de un adulto
I. Agudo, T. Souto-Moura
, L. Azevedo, R. Cavaco, N. Germano, L. Bento
Corresponding author
Unidade de Urgência Médica, Hospital de São José, Centro Hospitalar de Lisboa Central, EPE, Lisboa, Portugal
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Hidalgo, D. Mas, M. Rubio, P. Garcia-Hierro" "autores" => array:4 [ 0 => array:2 [ "nombre" => "F." "apellidos" => "Hidalgo" ] 1 => array:2 [ "nombre" => "D." "apellidos" => "Mas" ] 2 => array:2 [ "nombre" => "M." "apellidos" => "Rubio" ] 3 => array:2 [ "nombre" => "P." "apellidos" => "Garcia-Hierro" ] ] ] ] ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2173572716300017?idApp=WMIE" "url" => "/21735727/0000004000000003/v2_201703300141/S2173572716300017/v2_201703300141/en/main.assets" ] "en" => array:15 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Scientific Letter</span>" "titulo" => "Atypical hemolytic uremic syndrome in intensive care: Case report in an adult" "tieneTextoCompleto" => true "saludo" => "<span class="elsevierStyleItalic">Dear Editor</span>," "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "189" "paginaFinal" => "191" ] ] "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "I. Agudo, T. Souto-Moura, L. Azevedo, R. Cavaco, N. Germano, L. Bento" "autores" => array:6 [ 0 => array:2 [ "nombre" => "I." "apellidos" => "Agudo" ] 1 => array:4 [ "nombre" => "T." "apellidos" => "Souto-Moura" "email" => array:1 [ 0 => "teresasoutomoura@gmail.com" ] "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">*</span>" "identificador" => "cor0005" ] ] ] 2 => array:2 [ "nombre" => "L." "apellidos" => "Azevedo" ] 3 => array:2 [ "nombre" => "R." "apellidos" => "Cavaco" ] 4 => array:2 [ "nombre" => "N." "apellidos" => "Germano" ] 5 => array:2 [ "nombre" => "L." "apellidos" => "Bento" ] ] "afiliaciones" => array:1 [ 0 => array:2 [ "entidad" => "Unidade de Urgência Médica, Hospital de São José, Centro Hospitalar de Lisboa Central, EPE, Lisboa, Portugal" "identificador" => "aff0005" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Síndrome hemolítico urémico atípico en cuidados intensivos: caso clínico de un adulto" ] ] "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" => 692 "Ancho" => 926 "Tamanyo" => 175894 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Renal Biopsy (green masson tricromium stain) 400× – marked glomerular capillary stasis – glomerular thrombus.</p>" ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall">Thrombotic microangiopathy (TMA) is a pathologic process characterized by inflammation and thickening of wall vessels, endothelial edema, basement membrane detachment, intimal fibrosis and platelet thrombi formation with occlusion of vascular lumen. It affects mainly kidney and central nervous system microvasculature<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">1</span></a>; depending on the lesion distribution, two different syndromes are described: Thrombotic Thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS). Both are characterized by microangiopathic hemolytic anemia and thrombocytopenia.<a class="elsevierStyleCrossRefs" href="#bib0060"><span class="elsevierStyleSup">2,3</span></a> Neurological disorders are dominant in TTP whereas renal failure is dominant in HUS.</p><p id="par0010" class="elsevierStylePara elsevierViewall">HUS is denominated <span class="elsevierStyleItalic">typical</span> (90% of the cases) when caused by enteric shiga toxin-producing microorganisms, as <span class="elsevierStyleItalic">Escherichia coli</span> serotype O157:H7. The other rare cases are classified as <span class="elsevierStyleItalic">atypical</span> (<span class="elsevierStyleItalic">aHUS</span>), due to alternate complement pathway deregulation, or <span class="elsevierStyleItalic">secondary</span> to conditions such as pregnancy, autoimmune disease, invasive pneumococcal infections, HIV and H1N1 infections, cancer, malignant hypertension, and certain drugs.<a class="elsevierStyleCrossRefs" href="#bib0055"><span class="elsevierStyleSup">1,2</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">Most aHUS cases have a strong genetic component involving mutations and polymorphisms in the complement proteins genes.<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">4</span></a> It is more common in children and young adults and the prognosis is poor with high morbidity and mortality in acute phase and 50% of progression to chronic kidney disease.<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">1</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">The authors describe the case of a 35-year-old man who presented at the emergency department with fever, abdominal pain, nausea, bilious vomiting and decrease urine output for two weeks. He denied diarrhea and revealed history of intravenous drug abuse, under methadone program.</p><p id="par0025" class="elsevierStylePara elsevierViewall">At admission he was pale, with icteric sclera, hypertensive (197/108<span class="elsevierStyleHsp" style=""></span>mmHg) and tachypneic. Biochemistry revealed: normocytic normochromic anemia (Hb 6<span class="elsevierStyleHsp" style=""></span>g/dL); platelet count 132<span class="elsevierStyleHsp" style=""></span>×<span class="elsevierStyleHsp" style=""></span>10<span class="elsevierStyleSup">9</span><span class="elsevierStyleHsp" style=""></span>L<span class="elsevierStyleSup">−1</span>, acute kidney injury (Urea 81<span class="elsevierStyleHsp" style=""></span>mmol/L; Creatinine 1487<span class="elsevierStyleHsp" style=""></span>μmol/L); high Lactate dehydrogenase (LDH 23<span class="elsevierStyleHsp" style=""></span>μkat/L) and proteinuria (100<span class="elsevierStyleHsp" style=""></span>mg/dL). In the following hours the patient developed agitation, hallucinations and respiratory failure due to aspiration of gastric content, for what he was intubated and mechanically ventilated.</p><p id="par0030" class="elsevierStylePara elsevierViewall">At the Intensive Care Unit he presented thrombocytopenia (platelets 98<span class="elsevierStyleHsp" style=""></span>×<span class="elsevierStyleHsp" style=""></span>10<span class="elsevierStyleSup">9</span>), severe kidney impairment with anuria and started hemodialysis. The anemia study revealed hemolysis: schistocytes in peripheral blood smear, haptoglobin <7<span class="elsevierStyleHsp" style=""></span>mg/dL and raised LDH (26.7<span class="elsevierStyleHsp" style=""></span>μKat/L), and the patient underwent regular blood transfusion, during the first week. TMA diagnosis was admitted and daily plasmaferesis was initiated, with exchange of 1.5 plasma volume per session. He completed a total of eleven sessions, with renal function recovery, allowing the spacing of dialysis sessions, as well as normalization of platelets count and LDH levels.</p><p id="par0035" class="elsevierStylePara elsevierViewall">Complementary laboratory study excluded malignant hypertension, autoimmunity diseases, HIV and H1N1 infection. Shiga toxin was negative, C3 factor decreased, with no other changes in complement factors or respective antibodies. The activity of ADAMTS13 was normal without anti-ADAMTS13 antibodies (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>). The total body CT-scan excluded neoplasia. Kidney biopsy showed histopathological features of thrombotic microangiopathy (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>) and the genetic screening revealed a mutation in factor H.</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0040" class="elsevierStylePara elsevierViewall">During the hospitalization the patient presented high blood pressure, requiring labetalol perfusion followed by various antihypertensive agents. On the seventh day, he was successfully extubated. As infectious complications, he had <span class="elsevierStyleItalic">Staphylococcus epidermidis</span> bacteremia and <span class="elsevierStyleItalic">Stenotrophomonas maltophilia</span> on sputum smear, both resolved with the appropriate antibiotherapy.</p><p id="par0045" class="elsevierStylePara elsevierViewall">At the time of discharge, the platelet count was 275<span class="elsevierStyleHsp" style=""></span>×<span class="elsevierStyleHsp" style=""></span>10<span class="elsevierStyleSup">9</span>/L, LDH 4.48<span class="elsevierStyleHsp" style=""></span>μkat/L, Urea 27.8<span class="elsevierStyleHsp" style=""></span>mmol/L, Creatinine 223.6<span class="elsevierStyleHsp" style=""></span>μmol/L. Due to the persistence of kidney dysfunction the patient was transferred to nephrology ward where he continued on hemodialysis and started treatment with eculizumab, in the dosis of 900<span class="elsevierStyleHsp" style=""></span>mg weekly in the first month, followed by 1200<span class="elsevierStyleHsp" style=""></span>mg every 2 weeks thereafter.</p><p id="par0050" class="elsevierStylePara elsevierViewall">Hemolytic anemia, thrombocytopenia and acute renal failure as initial presentation were suggestive of TMA most likely HUS due to the magnitude of renal impairment. Subsequent finding of a regular ADAMTS13 activity excluded TTP.<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">5</span></a> Absence of diarrhea on presentation, negative Shiga toxin made less probable typical HUS diagnosis. Moreover, drugs and pathological conditions that cause secondary HUS were excluded.</p><p id="par0055" class="elsevierStylePara elsevierViewall">Atypical HUS associated with genetic or immune complement abnormalities was the most probable hypothesis. Activation of the alternative complement pathway with low serum C3, normal C4 and Factor B as well as absence of anti-factor H antibodies and normal levels of Factor H and I indicated a possible mutation in genes encoding C3, factor H or factor I,<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">6</span></a> that was confirmed by the genetic screening.</p><p id="par0060" class="elsevierStylePara elsevierViewall">Mutation in factor H was first identified in 1973 and it courses with low or normal plasma levels of factor H.<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">6</span></a> It is the most frequent genetic abnormality in aHUS patients (20–30%) and is associated with 50–70% risk of death or end stage renal disease in the first episode (<1 year) with a 50% risk of relapse and 75–90% risk of recurrence after kidney transplantation.<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">6</span></a></p><p id="par0065" class="elsevierStylePara elsevierViewall">Initial approach of aHUS requires red blood cells transfusion and hemodialysis, which were promptly initiated in this case. Platelet transfusion is contraindicated despite thrombocytopenia, except in cases of active bleeding, since it may exacerbate TMA.<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">6</span></a> Plasma therapy is the classical first choice treatment for all cases of aHUS.<a class="elsevierStyleCrossRefs" href="#bib0055"><span class="elsevierStyleSup">1,2,6</span></a> Plasmapheresis is prefered to plasma infusion because it assures the delivery of functional complement regulatory proteins and the removal of dysfunctional factors, with lower risk of volume overload. Should be initiated as early as possible, with exchange of 1.5 plasma volume per session, and continued until platelet count, hemoglobin, and LDH levels normalization.<a class="elsevierStyleCrossRefs" href="#bib0055"><span class="elsevierStyleSup">1,5–7</span></a></p><p id="par0070" class="elsevierStylePara elsevierViewall">Plasmapheresis has been the cornerstone of aHUS treatment since 1980 and was the only therapy available until 2010. A recent therapeutic alternative is eculizumab – a humanized monoclonal IgG antibody which binds to the C5 complement protein preventing the formation of C5b-9 (membrane attack complex) – already approved by the EMA and FDA.<a class="elsevierStyleCrossRefs" href="#bib0055"><span class="elsevierStyleSup">1,2,4,6</span></a> Two prospective phase II trials have demonstrated its efficacy on improving the platelet count and renal function of aHUS patients, including those with progressing TMA and those with long-standing, substantial kidney damage.<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">8</span></a> A posterior analysis confirmed the persistence of the clinical benefits after two years of follow-up.<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">9</span></a> Eculizumab was also associated with significant improvements in health-related quality of life.<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">8</span></a></p><p id="par0075" class="elsevierStylePara elsevierViewall">Barriers to eculizumab use include patient safety concerns, as infection with encapsulated bacterial organisms and the elevated cost.<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">2</span></a> On the other hand no cumulative toxicity or unexpected serious infections were observed, and survival was 100% on pivotal prospective studies,<a class="elsevierStyleCrossRefs" href="#bib0090"><span class="elsevierStyleSup">8–10</span></a> turning Eculizumab into a very promising option for aHUS patients treatment.</p><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0005">Funding</span><p id="par0080" class="elsevierStylePara elsevierViewall">None.</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Conflict of interest</span><p id="par0085" class="elsevierStylePara elsevierViewall">None.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:3 [ 0 => array:2 [ "identificador" => "sec0005" "titulo" => "Funding" ] 1 => array:2 [ "identificador" => "sec0010" "titulo" => "Conflict of interest" ] 2 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "multimedia" => array:2 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 692 "Ancho" => 926 "Tamanyo" => 175894 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Renal Biopsy (green masson tricromium stain) 400× – marked glomerular capillary stasis – glomerular thrombus.</p>" ] ] 1 => array:7 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:2 [ "leyenda" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">HIV: Human immunodeficiency virus; PCR: polymerase chain reaction; CFH: factor H; CFI: factor I; CFB: factor B; ADAMTS13: a desintegrin and metalloprotease with thrombospondin type1 domain 13; ANA: antinuclear antibody; dsDNA: double-stranded DNA; Sm: Smith; SSA: Sjögren syndrome A; SSB: Sjögren syndrome B; RNP: ribonucleic protein.</p>" "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=""><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Blood, urine and bronchial cultures \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Negative \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Shiga toxin \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Negative \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">HIV antibodies \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Negative \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">H1N1 (PCR) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Negative \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Streptococos pneumoniae</span> and <span class="elsevierStyleItalic">Legionella pneumophila</span> urine antigen \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Negative \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Antistreptolysin-O (ASO) titers \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Negative \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Complement study \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>C3 factor \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0.48<span class="elsevierStyleHsp" style=""></span>g/L [0.9–1.8] \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>C4, CHF, CHB, CHI \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Normal \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Anti-ADAMTS13 antibodies \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Negative \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">ADAMTS13 activity \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">73% (normal >6%) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">ANA, anti-dsDNA, anti-Sm, anti-SSA (Ro), anti-SSB (La), anti-RNP, anti-cardiolipine, anti-beta-2 glycoprotein I, anti-phospholipid antibodies \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Negative \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Serum protein electrophoresis \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Normal \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1381928.png" ] ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Complementary laboratory study.</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:10 [ 0 => array:3 [ "identificador" => "bib0055" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:3 [ "comentario" => "Available from: <span class="elsevierStyleInterRef" id="intr0005" href="http://dialnet.unirioja.es/servlet/articulo?codigo=4119823%26info=resumen%26idioma=SPA">http://dialnet.unirioja.es/servlet/articulo?codigo=4119823∈fo=resumen&idioma=SPA</span>" "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Actualización en síndrome hemolítico urémico atípico: diagnóstico y tratamiento. 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| Year/Month | Html | Total | |
|---|---|---|---|
| 2024 November | 9 | 12 | 21 |
| 2024 October | 49 | 41 | 90 |
| 2024 September | 53 | 29 | 82 |
| 2024 August | 55 | 48 | 103 |
| 2024 July | 36 | 27 | 63 |
| 2024 June | 57 | 49 | 106 |
| 2024 May | 39 | 38 | 77 |
| 2024 April | 62 | 41 | 103 |
| 2024 March | 47 | 38 | 85 |
| 2024 February | 41 | 39 | 80 |
| 2024 January | 31 | 40 | 71 |
| 2023 December | 45 | 50 | 95 |
| 2023 November | 48 | 28 | 76 |
| 2023 October | 51 | 43 | 94 |
| 2023 September | 45 | 38 | 83 |
| 2023 August | 64 | 21 | 85 |
| 2023 July | 47 | 38 | 85 |
| 2023 June | 61 | 18 | 79 |
| 2023 May | 77 | 38 | 115 |
| 2023 April | 49 | 21 | 70 |
| 2023 March | 89 | 27 | 116 |
| 2023 February | 65 | 33 | 98 |
| 2023 January | 54 | 24 | 78 |
| 2022 December | 63 | 31 | 94 |
| 2022 November | 67 | 43 | 110 |
| 2022 October | 56 | 34 | 90 |
| 2022 September | 55 | 33 | 88 |
| 2022 August | 83 | 47 | 130 |
| 2022 July | 59 | 29 | 88 |
| 2022 June | 45 | 15 | 60 |
| 2022 May | 48 | 43 | 91 |
| 2022 April | 89 | 32 | 121 |
| 2022 March | 54 | 45 | 99 |
| 2022 February | 51 | 30 | 81 |
| 2022 January | 82 | 41 | 123 |
| 2021 December | 82 | 76 | 158 |
| 2021 November | 94 | 46 | 140 |
| 2021 October | 115 | 74 | 189 |
| 2021 September | 48 | 35 | 83 |
| 2021 August | 46 | 42 | 88 |
| 2021 July | 37 | 40 | 77 |
| 2021 June | 41 | 32 | 73 |
| 2021 May | 53 | 60 | 113 |
| 2021 April | 164 | 87 | 251 |
| 2021 March | 73 | 47 | 120 |
| 2021 February | 63 | 35 | 98 |
| 2021 January | 69 | 33 | 102 |
| 2020 December | 65 | 31 | 96 |
| 2020 November | 48 | 33 | 81 |
| 2020 October | 54 | 43 | 97 |
| 2020 September | 47 | 19 | 66 |
| 2020 August | 49 | 19 | 68 |
| 2020 July | 42 | 37 | 79 |
| 2020 June | 39 | 28 | 67 |
| 2020 May | 56 | 13 | 69 |
| 2020 April | 40 | 22 | 62 |
| 2020 March | 36 | 11 | 47 |
| 2020 February | 73 | 47 | 120 |
| 2020 January | 42 | 25 | 67 |
| 2019 December | 57 | 24 | 81 |
| 2019 November | 61 | 31 | 92 |
| 2019 October | 55 | 15 | 70 |
| 2019 September | 35 | 18 | 53 |
| 2019 August | 38 | 22 | 60 |
| 2019 July | 40 | 24 | 64 |
| 2019 June | 32 | 16 | 48 |
| 2019 May | 51 | 21 | 72 |
| 2019 April | 29 | 18 | 47 |
| 2019 March | 28 | 24 | 52 |
| 2019 February | 28 | 18 | 46 |
| 2019 January | 29 | 46 | 75 |
| 2018 December | 43 | 48 | 91 |
| 2018 November | 72 | 52 | 124 |
| 2018 October | 27 | 22 | 49 |
| 2018 September | 17 | 3 | 20 |
| 2018 August | 15 | 4 | 19 |
| 2018 July | 15 | 7 | 22 |
| 2018 June | 15 | 8 | 23 |
| 2018 May | 14 | 1 | 15 |
| 2018 April | 14 | 6 | 20 |
| 2018 March | 15 | 2 | 17 |
| 2018 February | 16 | 6 | 22 |
| 2018 January | 14 | 5 | 19 |
| 2017 December | 16 | 6 | 22 |
| 2017 November | 17 | 4 | 21 |
| 2017 October | 16 | 7 | 23 |
| 2017 September | 7 | 4 | 11 |
| 2017 August | 9 | 3 | 12 |
| 2017 July | 9 | 2 | 11 |
| 2017 June | 20 | 11 | 31 |
| 2017 May | 20 | 4 | 24 |
| 2017 April | 27 | 5 | 32 |
| 2017 March | 19 | 10 | 29 |
| 2017 February | 11 | 4 | 15 |
| 2017 January | 9 | 4 | 13 |
| 2016 December | 7 | 9 | 16 |
| 2016 November | 7 | 20 | 27 |
| 2016 October | 13 | 20 | 33 |
| 2016 September | 21 | 8 | 29 |
| 2016 August | 36 | 6 | 42 |
| 2016 July | 5 | 0 | 5 |
Show all
