Original Article
Characteristics and Disease Course in a Cohort of Children With PFAPA Syndrome in the Community of Madrid, Spain
Características y evolución de una cohorte de niños con síndrome PFAPA en la Comunidad de Madrid
María de las Mercedes Ibáñez Alcaldea,
, Laura Caldevilla Asenjob, Cristina Calvo Reyc, Fernando García-Mon Marañésd, Daniel Blázquez Gamerob, Jesús Saavedra Lozanod, María Luisa Navarro Gómezd, Teresa Hernández-Sampelayo Matosd, Mar Santos Sebastiánd
Corresponding author
a Servicio de Pediatría, Hospital de Poniente, El Ejido, Almería, Spain
b Servicio de Pediatría, Hospital Universitario 12 de Octubre, Madrid, Spain
c Servicio de Pediatría, Hospital Universitario Severo Ochoa, Leganés, Madrid, Spain
d Servicio de Enfermedades Infecciosas Pediátricas, Hospital General Universitario Gregorio Marañón, Madrid, Spain
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(B) Frequency of associated symptoms.</p>" ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">PFAPA syndrome or <span class="elsevierStyleItalic">periodic fever with aphthous stomatitis, pharyngitis and adenitis</span>, was first described by Marshall in 1987,<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">1</span></a> and 2 years later received this acronym as its name.<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">2</span></a> It is a periodic febrile syndrome of unknown aetiology, related to the group of autoinflammatory diseases, and consists of recurrent febrile episodes associated with at least one of the following symptoms: pharyngitis, aphthous stomatitis afthosa or cervical adenitis. Age of presentation is early, usually before school age and tends to resolve itself over the years,<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">3</span></a> although long-term evolution has not been much studied.</p><p id="par0010" class="elsevierStylePara elsevierViewall">The real rate of PFAPA syndrome is unknown, since few population data have been published, but it is considered the most frequent of diseases with periodic fever and it is believed that probably all paediatricians will come across at least one case over the length of their career.<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">4</span></a> In this context, apart from describing its clinical findings, attempts have been made to describe the analytical pattern of the patients with this disease during febrile episodes so as to facilitate diagnosis, which is currently essentially clinical.</p><p id="par0015" class="elsevierStylePara elsevierViewall">Since its description 30 years ago, several treatments have been empirically studied due to its possible autoinflammatory aetiology. Corticosteroids are the most popular treatment during acute episodes, and tonsillectomy could be an effective treatment according to some studies.<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">5</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">The aim of this paper was to describe the epidemiological and clinical characteristics of a cohort of children diagnosed with PFAPA syndrome in our environment, analysing the analytical pattern presented during febrile episodes and assessing the role of tonsillectomy in treatment.</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Material and Methods</span><p id="par0025" class="elsevierStylePara elsevierViewall">A retrospective, multicentre cohort study. It included patients diagnosed with PFAPA syndrome, according to Thomas,<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">6</span></a> criteria (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>), whose diagnosis and/or follow-up was undertaken between 2009 and 2013 in 3 hospital centres of the Community of Madrid: the General University Hospital Gregorio Marañón, the University Hospital 12 de Octubre and the University Hospital Severo Ochoa. Cases with suspected hereditary periodic fever syndrome or a specific immunodeficiency, albeit not confirmed, were excluded, as were those patients with pharynx, blood and/or urine cultures in which positive isolation was obtained in the majority of febrile episodes, since these episodes could be related to recurrent infections.</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0030" class="elsevierStylePara elsevierViewall">The epidemiological and clinical characteristics were collected in all cases, including gender, ethnicity and geographical origin, age at the beginning of symptoms, age at diagnosis, duration and periodicity of febrile episodes and the presence of pharyngitis, adenitis, canker sores and/or other associated symptoms during the episode.</p><p id="par0035" class="elsevierStylePara elsevierViewall">Additional tests performed were recorded, both those during febrile episodes and those during symptom-free periods, in cases where they were available. The analytical data assessed were haemoglobin, platelet, leucocyte, neutrophil, lymphocyte, monocyte, eosinophil, reactive C protein (RCP) and erythrocyte sedimentation rates.</p><p id="par0040" class="elsevierStylePara elsevierViewall">Regarding the therapeutic interventions involved, the analysed variables were the age of symptom resolution, the response to corticosteroids in at least 24<span class="elsevierStyleHsp" style=""></span>h in the majority of episodes, the periodicity of the episodes after corticosteroid administration and the performing of tonsillectomy. In the case of tonsillectomy, age at surgery was also collected, as was the time of posterior follow-up, the appearance of new episodes and their frequency and the side effects attributed to them.</p><p id="par0045" class="elsevierStylePara elsevierViewall">In all patients clinical evolution during a minimum of 18 months was assessed.</p><p id="par0050" class="elsevierStylePara elsevierViewall">Analysis of data was undertaken with the SPSS 15.0 statistical programme, using descriptive analysis of frequencies and the Student's <span class="elsevierStyleItalic">T</span>-test for comparison of quantitative variables means with normal distribution, the Mann–Whitney <span class="elsevierStyleItalic">U</span> test for quantitative variables with non normal distribution, and the Chi-Square test for qualitative variables. A <span class="elsevierStyleItalic">p</span> value below .05 was considered significant throughout analysis.</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Results</span><p id="par0055" class="elsevierStylePara elsevierViewall">A total of 32 children diagnosed with PFAPA syndrome were included, of whom 21 were female (65.6%). The majority were Caucasian (87.5%), one (9.5%) was from Latin American and one was of gypsy ethnicity.</p><p id="par0060" class="elsevierStylePara elsevierViewall">Median age at onset of symptoms was 32 months (interquartile range [IQR] 24–44 months), whilst diagnosis was at 47.5 months (IQR 37–60 months). The median time which elapsed since the onset of medical symptoms until diagnosis of PFAPA syndrome was 12 months (IQR 6–25 months).</p><p id="par0065" class="elsevierStylePara elsevierViewall">The median periodicity of episode occurrences was 4 weeks (IQR 3–5 weeks), whilst the duration of fever in acute episodes was 4.5 days (IQR 4–5 days). The most frequently referred to symptom during these was acute pharyngitis, followed by cervical adenopathies (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>A). In 51.6% of cases the patients referred to other symptoms (associated with P, with the most common being abdominal pain (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>B).</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0070" class="elsevierStylePara elsevierViewall">In 28 cases (87.5%) analysis was available during the inter-episode period, and in 19 of these, at least another was performed during a febrile episode attributed to PFAPA syndrome. Findings from these analyses are reflected in <a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>. The statistically significant differences stand out in the rate of leukocytes, neutrophils and RCP between the acute phase and the inter-episode period.</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><p id="par0075" class="elsevierStylePara elsevierViewall">With regard to treatment, all cases received oral corticosteroids in the acute episodes after diagnosis. In 80.8% of cases the fever disappeared in under 24<span class="elsevierStyleHsp" style=""></span>h after administration.</p><p id="par0080" class="elsevierStylePara elsevierViewall">43.8% (14) of cases included underwent tonsillectomy, with a median age of 54.5 months (IQR 46.3–72.5 months). Median evolution prior to the surgical procedure was 24.5 months (IQR 13.5–35.8 months). In 11 of them (78.6%) symptoms were completely resolved after tonsillectomy and no new episodes presented, whilst in the 3 remaining patients there was a reduction in the frequency of the febrile episodes. Median follow-up after tonsillectomy was 8 months (IQR 6.5–25.5 months). In 2 cases adverse events from surgery were recorded. Both were postsurgical bleeding of relevance which required hospital admittance, but no blood transfusions.</p><p id="par0085" class="elsevierStylePara elsevierViewall">Of the 32 patients included in the study 56.3% had resolved the symptoms at the time of study, with a median age of 60 months (IQR 47–95 months). The median evolution time up to resolution was 25 months (IQR 16.8–33.5 months). The percentage of patients whose symptoms had been resolved were higher in those who underwent tonsillectomy (78.6% vs 38.9%, <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>.025), although there were no statistically significant differences during the resolution time between the patients who underwent tonsillectomy and those who did not (37.7 months [95% CI 16.5–59] vs 24.4 months [95% CI 14.1–34.8 months], <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>.683). No statistically significant differences were found between the epidemiological characteristics, age at diagnosis, age at resolution or episode characteristics between both groups.</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Discussion</span><p id="par0090" class="elsevierStylePara elsevierViewall">Most patients from this series were female, had begun attending the clinic in their third year of life and were diagnosed after approximately 12-month duration of their condition. The clinical characteristics of the cohort of this study did not differ from other previously published series. The febrile episodes occurred every 3–5 weeks, and during them a rise in leukocytes, neutrophils, RCP and erythrocyte sedimentation rates took place, with no association of acute bacterial symptoms. Tonsillectomy was performed on 14 of the patients, with resolution of their symptoms in 11 cases. Notwithstanding, no statistically significant differences were found in the resolution time between the groups whether or not tonsillectomy was performed although it was more prolonged in the children who had surgery, probably because those cases where symptoms resolved spontaneously with a shorter evolution time were less frequently candidates for surgery.</p><p id="par0095" class="elsevierStylePara elsevierViewall">Recurrent fever is a frequent finding in paediatrics, and its causes vary, with the most common being recurrent self-limiting viral processes. However, there is a group of illnesses which may cause fever from time to time, among which are auto inflammatory diseases.<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">7</span></a> Auto inflammatory diseases are included within the framework of primary immunodeficiences,<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">8</span></a> as conditions which occur from deregulation of the immune system.<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">9</span></a> The PFAPA syndrome is the most common of these,<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">7</span></a> but its real rate and pathogenesis are unknown. One Norwegian study published in 2013 estimated an incidence of 2.3 cases per 100,000 children under 5 years of age.<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">10</span></a> Small series of cases have been published in Spain,<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">11</span></a> the broadest of which, as far as we know, is the one presented herewith.</p><p id="par0100" class="elsevierStylePara elsevierViewall">Diagnosis of PFAPA syndrome was made based on Thomas’ criteria published in 1999,<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">6</span></a> and modified from those of Marshall of 1989,<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">2</span></a> which are currently those accepted by the Spanish Society of Paediatric Infectious Diseases.<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">7</span></a> Since this is a clinical diagnostic entity, they are not the only previously proposed criteria,<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">12</span></a> and probably the main source of conflict would be age at the beginning of symptoms which is usually earlier than 5 years of age. Data collected in this study therefore refers to patients whose symptoms began before they were 5, although some series have described cases where clinical symptoms began later.<a class="elsevierStyleCrossRefs" href="#bib0215"><span class="elsevierStyleSup">13–15</span></a></p><p id="par0105" class="elsevierStylePara elsevierViewall">The age of presentation of this cohort was similar to that of previously published studies, with a median age of between 11 months and 3 and a half years<a class="elsevierStyleCrossRefs" href="#bib0230"><span class="elsevierStyleSup">16–21</span></a>; the same is true of age at diagnosis which is situated between 3 and 8 years.<a class="elsevierStyleCrossRefs" href="#bib0235"><span class="elsevierStyleSup">17,18,20,21</span></a> Median time elapsed from the onset of symptoms to diagnosis, which in our cohort was 12 months, were slightly higher in 2 publications than our data: 2<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">17</span></a> and 3.2 years,<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">18</span></a> respectively. Greater familiarity with the disease and its higher rate in recent years has led to a shorter delay in diagnosing patients.</p><p id="par0110" class="elsevierStylePara elsevierViewall">Previously published studies present a periodicity of the episodes and a duration of fever in each episode similar to those of this series, oscillating in the majority of cases between 2 and 8 weeks, and 4 days, respectively.<a class="elsevierStyleCrossRefs" href="#bib0200"><span class="elsevierStyleSup">10,16–21</span></a> In most published cohort studies, the frequency of main symptoms is similar to that found in our study, with a predominance of pharyngitis (between 75% and 100% of cases), followed by cervical adenopathies (between 62% and 90% of cases) and canker sores (between 38% and 76%).<a class="elsevierStyleCrossRefs" href="#bib0230"><span class="elsevierStyleSup">16,17,19,21</span></a> The patients of this study presented with other symptoms not included in Thomas’ diagnostic criteria, which were mainly gastrointestinal, including stomach pain and nausea, headache and arthralgias, as similarly described by other authors.<a class="elsevierStyleCrossRefs" href="#bib0230"><span class="elsevierStyleSup">16,17,19,21</span></a></p><p id="par0115" class="elsevierStylePara elsevierViewall">In this series we observed a very slight reduction of haemoglobin during the febrile episodes, which was statistically significant but not clinically relevant. Similarly, an absence in the number of platelet increase was observed. These findings are consistent with previously published data.<a class="elsevierStyleCrossRefs" href="#bib0165"><span class="elsevierStyleSup">3,4</span></a> The raising of leucocyte, neutrophil and monocyte levels, as well as the reduction in absolute figures of lymphocytes in our cohort, has also been described in previous publications although on many occasions these changes are moderate and may remain within normal ranges.<a class="elsevierStyleCrossRefs" href="#bib0170"><span class="elsevierStyleSup">4,22</span></a> The raising of RCP during febrile episodes is usually more marked,<a class="elsevierStyleCrossRefs" href="#bib0170"><span class="elsevierStyleSup">4,21,23,24</span></a> just as is reflected in this series, whilst procalcitonin usually remains unaltered,<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">24</span></a> although this parameter was not sufficiently assessed in our study to be able to draw any conclusions in this regard.</p><p id="par0120" class="elsevierStylePara elsevierViewall">Initial recommended treatment in patients affected by PFAPA syndrome is the administration of oral corticosteroids during the acute episodes, in a single dose of 1<span class="elsevierStyleHsp" style=""></span>mg/kg of prednisone or its equivalent.<a class="elsevierStyleCrossRefs" href="#bib0175"><span class="elsevierStyleSup">5,7</span></a> 80.8% of the patients in this series stated their symptoms had ceased after administration of the treatment in the majority of episodes. In previous publications, the percentage of patients who responded after a single dose of oral corticosteroids were between 63%<a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">21</span></a> and 84%.<a class="elsevierStyleCrossRef" href="#bib0275"><span class="elsevierStyleSup">25</span></a> There are indication of a possible shortening of symptom-free episodes after administration<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">16</span></a> in some patients. The appearance of changes in periodicity of episodes could not be accurately assessed after the administration of corticosteroids, since this was not stated in the majority of records.</p><p id="par0125" class="elsevierStylePara elsevierViewall">Among alternative treatments, tonsillectomy has been the most highly studied. Out of the 14 patients of this cohort who underwent tonsillectomy, all experienced improvement of clinical symptoms, with resolution or reduction of frequency of febrile episodes in the remainder. A review of the Cochrane Library published in 2014,<a class="elsevierStyleCrossRef" href="#bib0280"><span class="elsevierStyleSup">26</span></a> based on 2 minor clinical trials where the symptoms were resolved in 63<a class="elsevierStyleCrossRef" href="#bib0285"><span class="elsevierStyleSup">27</span></a> and 100<a class="elsevierStyleCrossRef" href="#bib0290"><span class="elsevierStyleSup">28</span></a> of the patients who underwent surgery, respectively, concluded that tonsillectomy was an effective treatment but the quality of the evidence is moderate. In the observational studies published, the efficacy of tonsillectomy was between 50% and 100%.<a class="elsevierStyleCrossRefs" href="#bib0200"><span class="elsevierStyleSup">10,16,20,25,29,30</span></a> In this series, at the time of assessment, the symptoms had been resolved in 56.3% of cases and although the rate of resolution was higher in patients who had undergone tonsillectomy, there were no differences in time of evolution between those who had undergone tonsillectomies and those who had not. In fact, the resolution time in this series was higher in the children who had undergone tonsillectomy which could indicate that those whose symptoms took longer to resolve were referred to surgery. Furthermore, there is the factor of family anxiety towards recurring febrile episodes, which could impact the decision for surgery, but this factor is rarely assessed in studies, although often present.</p><p id="par0130" class="elsevierStylePara elsevierViewall">The main limitation of this work is its retrospective character, which impedes optimum assessment of the characteristics of the patient episodes due to loss of inherent information, and the possible bias of selection and information. Also, the number of patients, given the low rate of disease, impedes the creation of inferences. Another limitation is the variability in diagnosis of the PFAPA syndrome, due to the existence of many different published diagnostic criteria. We have tried to minimise this by establishing the Thomas criteria as inclusion criteria. Lastly, no viral studies were undertaken during the acute episodes, which could have facilitated an accurate differential diagnosis with recurrent infectious processes. However, it is a broad cohort compared with other published studies in our environment, and the selection criteria was intended to be as strict as possible.</p><p id="par0135" class="elsevierStylePara elsevierViewall">To conclude, a broad cohort of children with PFAPA syndrome was obtained in multicentre collaboration where it was confirmed that, in our environment, the children with this syndrome present several clinical and analytical characteristics similar to those described in the literature, with good response to corticosteroids. Knowledge of the analytical pattern in the febrile periods, where often leukocytosis, neutrophilia and a rise in RCP takes place, is essential to prevent unnecessary antibiotic treatments. Regarding tonsillectomy, this seems to be an effective treatment, which is suggested for those patients with a more torpid evolution. However, it is not exempt from side effects, which would have to be taken into account due to the self-limiting nature of the process. Each case should probably be individualised and this process considered as a therapeutic alternative. To determine the efficacy of surgical treatment it would be pertinent to carry out a random, but complex study, due to the low incidence of the disease.</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Conflict of Interests</span><p id="par0140" class="elsevierStylePara elsevierViewall">The authors have no conflict of interests to declare.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:10 [ 0 => array:3 [ "identificador" => "xres1268361" "titulo" => "Abstract" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Introduction" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Material and methods" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Results" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Conclusions" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec1173961" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres1268362" "titulo" => "Resumen" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0025" "titulo" => "Introducción" ] 1 => array:2 [ "identificador" => "abst0030" "titulo" => "Material y métodos" ] 2 => array:2 [ "identificador" => "abst0035" "titulo" => "Resultados" ] 3 => array:2 [ "identificador" => "abst0040" "titulo" => "Conclusiones" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec1173962" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:2 [ "identificador" => "sec0010" "titulo" => "Material and Methods" ] 6 => array:2 [ "identificador" => "sec0015" "titulo" => "Results" ] 7 => array:2 [ "identificador" => "sec0020" "titulo" => "Discussion" ] 8 => array:2 [ "identificador" => "sec0025" "titulo" => "Conflict of Interests" ] 9 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2017-09-10" "fechaAceptado" => "2017-10-28" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec1173961" "palabras" => array:5 [ 0 => "Hereditary inflammatory diseases" 1 => "Aphthous stomatitis" 2 => "Pharyngitis" 3 => "Adenopathy" 4 => "Tonsillectomy" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec1173962" "palabras" => array:5 [ 0 => "Enfermedades autoinflamatorias" 1 => "Estomatitis aftosa" 2 => "Faringitis" 3 => "Adenopatía" 4 => "Tonsilectomía" ] ] ] ] "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">PFAPA syndrome is an autoinflammatory disease whose diagnosis is mainly clinical. Several treatments have been proposed; among them, tonsillectomy could be an effective one.</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Material and methods</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Retrospective multicenter study. Patients included were diagnosed with PFAPA syndrome, according to the Thomas criteria, in 3 hospitals in Madrid between 2009 and 2013.</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Results</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Thirty-two cases were included. Median age at onset and at diagnosis were 32 months (IQR 24–44) and 47.5 months (IQR 37–60), respectively. There were increases in leukocytes (13,580/μl [IQR 8200–16,600] vs 8300/μl [IQR 7130–9650], <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>.005), neutrophils (9340/μl [IQR 5900–11,620] vs 3660/μl [IQR 2950–4580], <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>.002) and C-reactive protein (11.0<span class="elsevierStyleHsp" style=""></span>mg/dl [IQR 6.6–12.7] vs 0.2<span class="elsevierStyleHsp" style=""></span>mg/dl [IQR 0.1–0.6], <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>.003) during febrile episodes. In all, 80.8% of patients reported remission of symptoms within 24<span class="elsevierStyleHsp" style=""></span>h after oral corticosteroid therapy. Fourteen patients were tonsillectomised. In 11, the febrile episodes stopped while, in 3, the frequency was reduced; there were 2 cases of postoperative bleeding. The disease was resolved in 56.3% of the patients, at a median age of 60 months (IQR 47–95), with similar duration in patients who were tonsillectomised and those who were not.</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Conclusions</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">We present a large cohort of children with PFAPA syndrome, with clinical and analytical features similar to those described in the literature, and a good response to corticosteroids and a high resolution rate of symptoms after tonsillectomy.</p></span>" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Introduction" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Material and methods" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Results" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Conclusions" ] ] ] "es" => array:3 [ "titulo" => "Resumen" "resumen" => "<span id="abst0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Introducción</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">El síndrome PFAPA es una enfermedad autoinflamatoria de diagnóstico clínico. Se han propuesto diversos tratamientos; entre ellos, la tonsilectomía podría ser un tratamiento efectivo.</p></span> <span id="abst0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Material y métodos</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Estudio multicéntrico retrospectivo. Se incluyeron pacientes diagnosticados de síndrome PFAPA, según los criterios de Thomas, en 3 hospitales madrileños, entre 2009-2013.</p></span> <span id="abst0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Resultados</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Se incluyeron 32 casos. Las medianas de edad de inicio del cuadro y al diagnóstico fueron 32 meses (RIQ 24-44) y 47,5 meses (RIQ 37-60), respectivamente. Se hallaron incrementos en las cifras de leucocitos (13.580/μl [RIQ 8.200-16.600] vs 8.300/μl [RIQ 7.130-9.650], p<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0,005), neutrófilos (9.340/μl [RIQ 5.900-11.620] vs 3.660/μl [RIQ 2.950-4.580], p<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0,002) y proteína C reactiva (11,0<span class="elsevierStyleHsp" style=""></span>mg/dl [RIQ 6,6-12,7] vs 0,2<span class="elsevierStyleHsp" style=""></span>mg/dl [RIQ 0,1-0,6], p<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0,003) durante los episodios febriles, respecto a los periodos libres de síntomas. El 80,8% refería remisión de los síntomas en 24<span class="elsevierStyleHsp" style=""></span>h tras corticoterapia oral. Fueron tonsilectomizados 14 pacientes. En 11 cesaron los episodios febriles, mientras que en 3 se redujo su frecuencia; hubo 2 sangrados posquirúrgicos como complicación. El cuadro se había resuelto en el 56,3% de los pacientes, a una mediana de edad de 60 meses (RIQ 47-95), con una duración similar entre los pacientes que fueron tonsilectomizados y los que no.</p></span> <span id="abst0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Conclusiones</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">Se presenta una cohorte amplia de niños con síndrome de PFAPA en la que se confirma que, en nuestro medio, los niños con este síndrome presentan unas características clínicas y analíticas similares a las descritas en la literatura, con buena respuesta a corticoterapia y elevada resolución de la clínica tras la amigdalectomía.</p></span>" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0025" "titulo" => "Introducción" ] 1 => array:2 [ "identificador" => "abst0030" "titulo" => "Material y métodos" ] 2 => array:2 [ "identificador" => "abst0035" "titulo" => "Resultados" ] 3 => array:2 [ "identificador" => "abst0040" "titulo" => "Conclusiones" ] ] ] ] "NotaPie" => array:2 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as: Ibáñez Alcalde MM, Caldevilla Asenjo L, Calvo Rey C, García-Mon Marañés F, Blázquez Gamero D, Saavedra Lozano J, et al. Características y evolución de una cohorte de niños con síndrome PFAPA en la Comunidad de Madrid. Reumatol Clin. 2019;15:355–359.</p>" ] 1 => array:2 [ "etiqueta" => "☆☆" "nota" => "<p class="elsevierStyleNotepara" id="npar0010">This paper was presented as scientific communication at the 7th Congress of the Spanish Society of Paediatric Infectious Diseases, which took place in Santiago de Compostela from 6th to 8th March 2014.</p>" ] ] "multimedia" => array:3 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 2276 "Ancho" => 2344 "Tamanyo" => 200556 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">(A) Observed frequency of the signs included in the diagnostic criteria of Thomas. (B) Frequency of associated symptoms.</p>" ] ] 1 => array:8 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at1" "detalle" => "Table " "rol" => "short" ] ] "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=""><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">Recurrent fever at onset before 5 years of age</span> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">Symptoms without any catarrhal phase with at least one out of:</span> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Aphthous stomatitis \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Cervical adenitis \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Pharyngitis \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">Exclusion of cyclical neutropenia</span> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">Absence of symptoms between episodes</span> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">Normal growth and development</span> \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab2169545.png" ] ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">Thomas’ Diagnostic Criteria for PFAPA Syndrome.</p>" ] ] 2 => array:8 [ "identificador" => "tbl0010" "etiqueta" => "Table 2" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at2" "detalle" => "Table " "rol" => "short" ] ] "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"><th 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" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th 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" scope="col" style="border-bottom: 2px solid black">Analysis between eepisodesMedian (IQR) \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th 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" scope="col" style="border-bottom: 2px solid black">Analyses in febrile episodeMedian (IQR) \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th 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" scope="col" style="border-bottom: 2px solid black"><span class="elsevierStyleItalic">p</span> \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Hb (g/dl) \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="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">12.7 (12.4–13.2) \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="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">12.1 (11.8–12.8) \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="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">.023 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Platelets/μl \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="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">317,000 (265,000–379,000) \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="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">241,000 (211,000–347,000) \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="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">.006 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Leukocytes/μl \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="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">8300 (7130–9650) \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="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">13,580 (8200–16,600) \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="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">.005 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Neutrophils/μl \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="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">3660 (2950–4580) \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="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">9340 (5900–11,620) \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="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">.002 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Lymphocytes/μl \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="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">3250 (2130–4410) \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="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2740 (1950–3630) \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="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">.050 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Monocytes/μl \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="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">550 (490–780) \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="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1100 (720–1580) \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="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">.007 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Eosinophils/μl \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="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">200 (100–300) \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="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">100 (50–140) \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="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">.011 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">RCP (mg/dl) \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="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">.2 (.1–.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="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">11.0 (6.6–12.7) \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="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">.003 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">ESR (mm/early morning) \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="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">5.0 (2.8–9.5) \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="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">34.0 (28.0–47.0) \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="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">.042 \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab2169546.png" ] ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">Comparison of Analytical Values of Children With PFAPA Syndrome at the Time of Acute Episode and Inter-episode Period.</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0015" "bibliografiaReferencia" => array:30 [ 0 => array:3 [ "identificador" => "bib0155" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Syndrome of periodic fever, pharyngitis, and aphthous stomatitis" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "G.S. 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| 2023 May | 48 | 39 | 87 |
| 2023 April | 43 | 13 | 56 |
| 2023 March | 67 | 20 | 87 |
| 2023 February | 58 | 25 | 83 |
| 2023 January | 36 | 15 | 51 |
| 2022 December | 81 | 31 | 112 |
| 2022 November | 42 | 28 | 70 |
| 2022 October | 87 | 51 | 138 |
| 2022 September | 46 | 21 | 67 |
| 2022 August | 37 | 50 | 87 |
| 2022 July | 37 | 45 | 82 |
| 2022 June | 39 | 36 | 75 |
| 2022 May | 55 | 36 | 91 |
| 2022 April | 82 | 40 | 122 |
| 2022 March | 54 | 39 | 93 |
| 2022 February | 80 | 27 | 107 |
| 2022 January | 73 | 38 | 111 |
| 2021 December | 30 | 43 | 73 |
| 2021 November | 29 | 48 | 77 |
| 2021 October | 39 | 59 | 98 |
| 2021 September | 38 | 45 | 83 |
| 2021 August | 23 | 38 | 61 |
| 2021 July | 13 | 20 | 33 |
| 2021 June | 31 | 26 | 57 |
| 2021 May | 41 | 37 | 78 |
| 2021 April | 114 | 89 | 203 |
| 2021 March | 54 | 31 | 85 |
| 2021 February | 49 | 19 | 68 |
| 2021 January | 48 | 22 | 70 |
| 2020 December | 47 | 18 | 65 |
| 2020 November | 23 | 19 | 42 |
| 2020 October | 22 | 26 | 48 |
| 2020 September | 34 | 19 | 53 |
| 2020 August | 25 | 34 | 59 |
| 2020 July | 17 | 17 | 34 |
| 2020 June | 17 | 9 | 26 |
| 2020 May | 32 | 27 | 59 |
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