Asthma control and exacerbations in patients with severe asthma treated with omalizumab in Portugal

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Winck, R. Camacho, N. Ambrosino" "autores" => array:3 [ 0 => array:2 [ "Iniciales" => "J." "apellidos" => "Winck" ] 1 => array:2 [ "Iniciales" => "R." "apellidos" => "Camacho" ] 2 => array:2 [ "Iniciales" => "N." 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Y¿lmaz, N. Bayraktar, K. Ceyhan, D. Seçil, S. Yüksel, Z. M¿s¿rl¿gil, S. Bavbek" "autores" => array:7 [ 0 => array:2 [ "nombre" => "¿." "apellidos" => "Y¿lmaz" ] 1 => array:2 [ "Iniciales" => "N." "apellidos" => "Bayraktar" ] 2 => array:2 [ "Iniciales" => "K." "apellidos" => "Ceyhan" ] 3 => array:2 [ "Iniciales" => "D." "apellidos" => "Seçil" ] 4 => array:2 [ "Iniciales" => "S." "apellidos" => "Yüksel" ] 5 => array:2 [ "Iniciales" => "Z." "apellidos" => "M¿s¿rl¿gil" ] 6 => array:2 [ "Iniciales" => "S." "apellidos" => "Bavbek" ] ] ] ] ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/X0873215915459700?idApp=UINPBA00004E" "url" => "/08732159/0000002100000006/v0_201604141141/X0873215915459700/v0_201604141141/en/main.assets" ] "en" => array:14 [ "idiomaDefecto" => true "titulo" => "Asthma control and exacerbations in patients with severe asthma treated with omalizumab in Portugal" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "327" "paginaFinal" => "333" ] ] "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "A.S. Sousa, A.M. Pereira, J.A. Fonseca, L.F. Azevedo, C. Abreu, A. Arrobas, T. Calvo, M.J. Silvestre, L. Cunha, H. Falcão, M. Drummond, L. Geraldes, C. Loureiro" "autores" => array:13 [ 0 => array:3 [ "Iniciales" => "A.S." "apellidos" => "Sousa" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "affa" ] ] ] 1 => array:3 [ "Iniciales" => "A.M." "apellidos" => "Pereira" "referencia" => array:3 [ 0 => array:2 [ "etiqueta" => "b" "identificador" => "affb" ] 1 => array:2 [ "etiqueta" => "c" "identificador" => "affc" ] 2 => array:2 [ "etiqueta" => "d" "identificador" => "affd" ] ] ] 2 => array:4 [ "Iniciales" => "J.A." "apellidos" => "Fonseca" "email" => array:1 [ 0 => "fonseca.ja@gmail.com" ] "referencia" => array:4 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "affa" ] 1 => array:2 [ "etiqueta" => "*" "identificador" => "cor1" ] 2 => array:2 [ "etiqueta" => "c" "identificador" => "affc" ] 3 => array:2 [ "etiqueta" => "d" "identificador" => "affd" ] ] ] 3 => array:3 [ "Iniciales" => "L.F." "apellidos" => "Azevedo" "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "affa" ] 1 => array:2 [ "etiqueta" => "d" "identificador" => "affd" ] ] ] 4 => array:3 [ "Iniciales" => "C." "apellidos" => "Abreu" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "e" "identificador" => "affe" ] ] ] 5 => array:3 [ "Iniciales" => "A." "apellidos" => "Arrobas" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "f" "identificador" => "afff" ] ] ] 6 => array:3 [ "Iniciales" => "T." "apellidos" => "Calvo" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "g" "identificador" => "affg" ] ] ] 7 => array:3 [ "Iniciales" => "M.J." "apellidos" => "Silvestre" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "g" "identificador" => "affg" ] ] ] 8 => array:3 [ "Iniciales" => "L." "apellidos" => "Cunha" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "h" "identificador" => "affh" ] ] ] 9 => array:3 [ "Iniciales" => "H." "apellidos" => "Falcão" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "h" "identificador" => "affh" ] ] ] 10 => array:3 [ "Iniciales" => "M." "apellidos" => "Drummond" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "i" "identificador" => "affi" ] ] ] 11 => array:3 [ "Iniciales" => "L." "apellidos" => "Geraldes" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "j" "identificador" => "affj" ] ] ] 12 => array:3 [ "Iniciales" => "C." "apellidos" => "Loureiro" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "k" "identificador" => "affk" ] ] ] ] "afiliaciones" => array:11 [ 0 => array:3 [ "entidad" => "Center for Research in Health Technologies and Information Systems, Faculdade de Medicina da Universidade do Porto, Porto, Portugal" "etiqueta" => "a" "identificador" => "affa" ] 1 => array:3 [ "entidad" => "Allergy Department, Centro Hospitalar de São João, EPE, Porto, Portugal" "etiqueta" => "b" "identificador" => "affb" ] 2 => array:3 [ "entidad" => "Allergy Unit, CUF Porto Instituto e CUF Porto Hospital, Portugal" "etiqueta" => "c" "identificador" => "affc" ] 3 => array:3 [ "entidad" => "Health Information and Decision Sciences Department, Faculdade de Medicina da Universidade do Porto, Porto, Portugal" "etiqueta" => "d" "identificador" => "affd" ] 4 => array:3 [ "entidad" => "Allergy Department, Hospital Pedro Hispano Unidade Local de Saúde de Matosinhos, EPE, Matosinhos, Portugal" "etiqueta" => "e" "identificador" => "affe" ] 5 => array:3 [ "entidad" => "Pulmonology Department, Hospital Geral de Coimbra Centro Hospitalar e Universitário de Coimbra, EPE, Coimbra, Portugal" "etiqueta" => "f" "identificador" => "afff" ] 6 => array:3 [ "entidad" => "Pulmonology Department, Centro Hospitalar de Trás os Montes e Alto Douro, EPE, Vila Real, Portugal" "etiqueta" => "g" "identificador" => "affg" ] 7 => array:3 [ "entidad" => "Allergy Department, Centro Hospitalar do Porto, EPE, Porto, Portugal" "etiqueta" => "h" "identificador" => "affh" ] 8 => array:3 [ "entidad" => "Pulmonology Department, Centro Hospitalar de São João, EPE, Porto, Portugal" "etiqueta" => "i" "identificador" => "affi" ] 9 => array:3 [ "entidad" => "Allergy Department, Centro Hospitalar do Alto Ave, EPE, Guimarães, Portugal" "etiqueta" => "j" "identificador" => "affj" ] 10 => array:3 [ "entidad" => "Pulmonology Department, Centro Hospitalar e Universitário de Coimbra, EPE, Coimbra, Portugal" "etiqueta" => "k" "identificador" => "affk" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor1" "etiqueta" => "*" "correspondencia" => "Corresponding author. fonseca.ja@gmail.com" ] ] ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:8 [ "identificador" => "fig1" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "copyright" => "Elsevier España" "figura" => array:1 [ 0 => array:4 [ "imagen" => "320v21n06-90445971fig1.jpg" "Alto" => 2290 "Ancho" => 3005 "Tamanyo" => 247025 ] ] "descripcion" => array:1 [ "en" => "Distribution of the number of exacerbations (A) unscheduled healthcare utilization (B) and increases in OCS intake (C) in the 12-month follow-up period." ] ] ] "textoCompleto" => "<a name="sec0005" class="elsevierStyleCrossRefs"></a>IntroductionSevere asthma was recently defined by the European Respiratory Society/American Thoracic Society as “asthma which requires treatment with high dose inhaled corticosteroids plus a second controller (and/or systemic corticosteroids) to prevent it from becoming ‘uncontrolled’ or asthma which remains ‘uncontrolled’ despite this therapy”.<a href="#bib24" class="elsevierStyleCrossRefs">1</a> It is estimated that up to 15% of asthma patients may have severe asthma.<a href="#bib25" class="elsevierStyleCrossRefs">2</a> These few patients account for a disproportionate part of the burden and healthcare costs associated with asthma.<a href="#bib26" class="elsevierStyleCrossRefs">3</a>Omalizumab is a humanized anti-IgE antibody recommended for treating severe allergic IgE-mediated persistent asthma as an add-on to optimized standard therapy in people aged 6 years or older who need continuous or frequent treatment with oral corticosteroids (OCS) (defined as 4 or more courses in the previous year).<a href="#bib27" class="elsevierStyleCrossRefs">4</a> Previous studies in adults have shown that treatment with omalizumab is associated with an improvement in the control of asthma symptoms, with decreased frequency and use of rescue medication and OCS, and with a reduction in the total asthma-related emergency visits (including hospital admissions, emergency department visits and unscheduled visits to the doctor).<a href="#bib27" class="elsevierStyleCrossRefs">4</a> However, most of these data come from clinical trials, primarily designed to assess treatment efficacy in highly selected patients; this poses problems when generalizing to daily clinical practice. Real-life prospective studies, presented as a pragmatic approach to everyday clinical practice, are fundamental to assess the impact of omalizumab treatment in patients with severe asthma and should contribute to future informed decisions about this treatment. In Portugal, although four studies described outcomes of omalizumab treatment in real-life settings,<a href="#bib28" class="elsevierStyleCrossRefs">5</a>, <a href="#bib29" class="elsevierStyleCrossRefs">6</a>, <a href="#bib30" class="elsevierStyleCrossRefs">7</a>, <a href="#bib31" class="elsevierStyleCrossRefs">8</a> only one is prospective and it was conducted in a single healthcare unit.The aim of this prospective multicentre study was to assess the clinical effect of omalizumab in Portuguese patients with severe persistent allergic asthma, specifically concerning asthma control and exacerbations.<a name="sec0010" class="elsevierStyleCrossRefs"></a>Methods<a name="sec0015" class="elsevierStyleCrossRefs"></a>DesignThis was a multicentre, descriptive, observational, prospective study, conducted during routine asthma care. The target population was individuals treated with omalizumab for severe persistent asthma.<a name="sec0020" class="elsevierStyleCrossRefs"></a>Setting and participantsThe study was conducted in seven Pulmonology and Allergology departments from six hospitals in north and centre mainland Portugal. In each unit, all asthma patients under treatment with omalizumab were included, regardless of the age, length of previous therapy with omalizumab or actual treatment schedule. All patients had omalizumab treatment approved by the therapeutic commission and hospital administration, as required in Portuguese hospitals. Minimal criteria for approval of omalizumab treatment for asthma are uncontrolled, severe persistent, allergic asthma, with frequent exacerbations.<a name="sec0025" class="elsevierStyleCrossRefs"></a>Data collectionData were collected at each routine visit for omalizumab administration, during 12 consecutive months. In the participating centres, omalizumab was administered at 2- or 4-week intervals with doses based on IgE serum levels and body weight, as recommended by EMEA – European Medicines Agency.<a href="#bib32" class="elsevierStyleCrossRefs">9</a> A structured form, to be filled by both the patient and the nurse responsible for omalizumab administration, was developed in order to standardize data collection at the different study sites. This form included questions on asthma worsening, medication intake, healthcare resources utilization and work/school absenteeism; information on side effects was possibly related with the previous treatment administration. The Control of Allergic Rhinitis and Asthma Test (CARAT)<a href="#bib33" class="elsevierStyleCrossRefs">10</a>, <a href="#bib34" class="elsevierStyleCrossRefs">11</a> was also part of the form.Data collection spanned from January 2011 to December 2013 in the different departments (Additional file 1).<a name="sec0030" class="elsevierStyleCrossRefs"></a>OutcomesAsthma and rhinitis control was defined by CARAT global score >24. CARAT lower airways score ≥16 and upper airways score >8 were the cut-off values for control of, respectively, the lower and upper airways only.Asthma exacerbation was defined as having unscheduled healthcare utilization or increases in OCS intake because of asthma. Asthma worsening, unscheduled healthcare utilization and increases in oral corticosteroid intake were based on a positive answer to the questions: “In the last 3 days, have you felt your asthma getting worse?”; “Since the last administration, have you had any unscheduled healthcare visit or emergency room visit because of your asthma?” and “In the last 3 days, did you need to start or increase oral corticosteroid intake?”, respectively.<a name="sec0035" class="elsevierStyleCrossRefs"></a>Statistical analysisStatistical analyses were performed using IBM SPSS Statistics version 21 (2012 SPSS Inc., IBM Company, Chicago, US). Categorical and continuous variables were analyzed using descriptive statistics as appropriate. Survival analysis was used to assess the time until the first exacerbation. Generalized Estimating Equations, taking into account the multiple measurements in this longitudinal design, were used to assess variations in control scores over time; a Wald Chi-square test with a p-value of <0.05 was considered statistically significant. As CARAT evaluates a 4-week period, control scores were analyzed for visits with at least a 4-week interval.<a name="sec0040" class="elsevierStyleCrossRefs"></a>ResultsA total of 48 adults with severe persistent allergic asthma were included (<a href="#t0005" class="elsevierStyleCrossRefs">Table 1</a>). Patients were under treatment with omalizumab for between 0 and 67 months, most for more than 3 years (median, 45 months). Most patients (n = 31, 65%) were prospectively followed for 12 months and five were followed for less than 9 months (Additional file 1). During the study, the median (min–max) number of medical visits for each patient was 14 (7–28). Side effects were reported in 5% of the visits (Additional file 2); thirty-two (67%) patients did not report any side effect during the study.Table 1. Characteristics of the study population (n = 48).<a name="t0005" class="elsevierStyleCrossRefs"></a><table><tr align="left"><td>Female (n, %)</td><td>36</td><td>77</td></tr><tr align="left"><td colspan="3"> </td></tr><tr align="left"><td>Age (mean, SD)</td><td>52</td><td>10</td></tr><tr align="left"><td colspan="3"> </td></tr><tr align="left"><td colspan="3">Hospital units (n, %)</td></tr><tr align="left"><td>Centro Hospitalar e Universitário de Coimbra, EPE – Pulmonology</td><td>15</td><td>31</td></tr><tr align="left"><td>Centro Hospitalar São João, EPE – Allergology</td><td>12</td><td>39</td></tr><tr align="left"><td>Centro Hospitalar São João, EPE – Pulmonology</td><td>8</td><td>26</td></tr><tr align="left"><td>Centro Hospitalar do Porto – Allergology</td><td>6</td><td>13</td></tr><tr align="left"><td>Centro Hospitalar de Trás-os-Montes e Alto Douro – Pulmonology</td><td>4</td><td>8</td></tr><tr align="left"><td>Hospital Pedro Hispano – Allergology</td><td>2</td><td>4</td></tr><tr align="left"><td>Centro Hospitalar do Alto Ave – Allergology</td><td>1</td><td>2</td></tr><tr align="left"><td colspan="3"> </td></tr><tr align="left"><td>Follow-up period, months (median, min–max)</td><td>12</td><td>3–12</td></tr><tr align="left"><td colspan="3"> </td></tr><tr align="left"><td>Visits with reported OCS intake (mean% per patient, SD)</td><td>15</td><td>32</td></tr></table>SD – standard deviation; OCS – oral corticosteroid. <a name="sec0045" class="elsevierStyleCrossRefs"></a>Asthma controlCARAT scores were analyzed for visits with at least a 4-week interval in a total of 414 visits. During the study period, asthma was controlled in 34% of the visits; the mean (SD) CARAT score was 20.4 (7.5). There was no statistically significant variation in any of the CARAT mean scores during the 12-month follow-up period (p > 0.05).<a name="sec0050" class="elsevierStyleCrossRefs"></a>Asthma exacerbationsDuring follow-up, 26 patients (54%) had at least one asthma exacerbation (<a href="#f0005" class="elsevierStyleCrossRefs">Figure 1</a>); the 12-month rate of asthma exacerbations per patient was 1.7–1.3 increases with OCS intake and 0.6 unscheduled healthcare utilizations. The first exacerbation occurred on average (mean [95% CI]) 7.2 (5.9–8.6) months after entering the study. There was no clear pattern of distribution of asthma exacerbations and control throughout the year (<a href="#f0010" class="elsevierStyleCrossRefs">Figure 2</a>).<a name="f0005" class="elsevierStyleCrossRefs"></a><img src="320v21n06-90445971fig1.jpg" alt="Distribution of the number of exacerbations (A) unscheduled healthcare utilization (B) and increases in OCS intake (C) in the 12-month follow-up period."></img>Figure 1. Distribution of the number of exacerbations (A) unscheduled healthcare utilization (B) and increases in OCS intake (C) in the 12-month follow-up period.<a name="f0010" class="elsevierStyleCrossRefs"></a><img src="320v21n06-90445971fig2.jpg" alt="(A) Percentage of visits reporting controlled asthma and exacerbations according to the month of the year (all patients included). (B) Reports of controlled asthma and exacerbations during follow-up, per patient. In (B) numbers on the right indicate total months of follow-up; continuous grey lines represent the follow-up period and dashed grey lines interruptions in omalizumab treatment; red dots represent visits with report of exacerbation and blue dashes visits with CARAT global score >24–data from the 20 patients treated with omalizumab in Centro Hospitalar São João, EPE."></img>Figure 2. (A) Percentage of visits reporting controlled asthma and exacerbations according to the month of the year (all patients included). (B) Reports of controlled asthma and exacerbations during follow-up, per patient. In (B) numbers on the right indicate total months of follow-up; continuous grey lines represent the follow-up period and dashed grey lines interruptions in omalizumab treatment; red dots represent visits with report of exacerbation and blue dashes visits with CARAT global score >24–data from the 20 patients treated with omalizumab in Centro Hospitalar São João, EPE.Thirty-three (69%) participants reported at least one period of worsening of asthma symptoms without needing unscheduled medical care or OCS intake. Eight (17%) had more than four periods of worsening of asthma.<a name="sec0055" class="elsevierStyleCrossRefs"></a>Oral corticosteroids intakeFourteen patients (29%) took OCS because of asthma at least once during the follow-up. Seven patients were taking daily OCS in the first visit and five of them took OCS during the full length of the study, in a mean (SD) dosage of 18.9 (4.4) mg prednisolone/day. Comparing the first and the last trimesters of the study, seven patients reduced the daily dosage of OCS, four patients reported a dosage increase, and two had no variation. Overall, the daily dosage of OCS had a non-significant reduction of 41.6% (<a href="#f0015" class="elsevierStyleCrossRefs">Figure 3</a>). One patient had a follow-up inferior to two trimesters and was not considered for comparison purposes.<a name="f0015" class="elsevierStyleCrossRefs"></a><img src="320v21n06-90445971fig3.jpg" alt="Mean dosage of oral corticosteroids intake in the first and last trimester of the follow-up year (considering the 13 patients with OCS intake), (A) Overall reduction (B) Per patient. In (B) arrows represent the dose variation from the first to the last trimester; red lines represent increases and blue lines decrease in the dosage of oral corticosteroid intake; and dots represent no variation in the dosage."></img>Figure 3. Mean dosage of oral corticosteroids intake in the first and last trimester of the follow-up year (considering the 13 patients with OCS intake), (A) Overall reduction (B) Per patient. In (B) arrows represent the dose variation from the first to the last trimester; red lines represent increases and blue lines decrease in the dosage of oral corticosteroid intake; and dots represent no variation in the dosage.<a name="sec0060" class="elsevierStyleCrossRefs"></a>DiscussionDuring the 12-month follow-up, patients with severe persistent allergic asthma treated with omalizumab had their asthma controlled in 34% of the visits; 2/3 had no need for unscheduled medical care due to asthma and 46% remained exacerbation free. The asthma exacerbation rate was 1.7 exacerbations per patient per year (the rate of treatment courses with OCS was 1.3 and of unscheduled healthcare utilizations was 0.6).Previously published observational studies performed in real-life settings reported that omalizumab is effective in the treatment of patients with severe persistent allergic asthma.<a href="#bib28" class="elsevierStyleCrossRefs">5</a>, <a href="#bib35" class="elsevierStyleCrossRefs">12</a>, <a href="#bib36" class="elsevierStyleCrossRefs">13</a>, <a href="#bib37" class="elsevierStyleCrossRefs">14</a>, <a href="#bib38" class="elsevierStyleCrossRefs">15</a>, <a href="#bib39" class="elsevierStyleCrossRefs">16</a>, <a href="#bib40" class="elsevierStyleCrossRefs">17</a>, <a href="#bib41" class="elsevierStyleCrossRefs">18</a>The present study showed that the proportion of patients with good asthma control in these patients with severe persistent allergic asthma was stable. The asthma control score did not change significantly during the follow-up period probably because patients were already under treatment with omalizumab at enrolment. This ‘stability’ concurs with several studies<a href="#bib28" class="elsevierStyleCrossRefs">5</a>, <a href="#bib39" class="elsevierStyleCrossRefs">16</a> that reported improvements in asthma control in the first 16 weeks of omalizumab treatment and a tendency to stabilize the effect in the following months. Previously published studies using CARAT questionnaire to assess the control of asthma and rhinitis in other settings found a mean (SD) CARAT score of 17.8 (6.4) in a community of inner Portugal,<a href="#bib42" class="elsevierStyleCrossRefs">19</a> 17.8 (0.2) in patients followed in the Allergology Department of a University Hospital<a href="#bib43" class="elsevierStyleCrossRefs">20</a> and 17.2 (6.7) in patients referred to the Allergy outpatient clinic from a district hospital.<a href="#bib44" class="elsevierStyleCrossRefs">21</a> The mean CARAT score found in the present study for patients with severe asthma is similar to those found in patients with non-severe asthma, suggesting a positive effect of omalizumab treatment.The rate of 0.6 emergency visits per patient-year observed in the present study is inferior to the rates reported by Molimard and co-workers – 1.1 emergency visits per patient-year after a follow-up of more than 5 months,<a href="#bib41" class="elsevierStyleCrossRefs">18</a> and by Cazzola and co-workers – 1.2 visits per patient-year after a follow-up of 12 months.<a href="#bib35" class="elsevierStyleCrossRefs">12</a>The exacerbation rate observed in the present study is lower than the rates reported in France<a href="#bib41" class="elsevierStyleCrossRefs">18</a> and in the PERSIST study<a href="#bib39" class="elsevierStyleCrossRefs">16</a> but greater than those of Germany,<a href="#bib40" class="elsevierStyleCrossRefs">17</a> Italy,<a href="#bib35" class="elsevierStyleCrossRefs">12</a> Ireland<a href="#bib37" class="elsevierStyleCrossRefs">14</a> and Spain,<a href="#bib38" class="elsevierStyleCrossRefs">15</a> in similar studies. Overall, in our study, the frequency of asthma exacerbations during one-year omalizumab treatment was lower than expected for these severe patients.<a href="#bib45" class="elsevierStyleCrossRefs">22</a> However, in spite of being treated with omalizumab, five patients had ≥5 exacerbations. We could speculate whether before starting omalizumab the asthma control in these patients was even worse or if the treatment with omalizumab was ineffective and should be discontinued.Previous work found that omalizumab had a marked effect in the reduction of seasonal peaks of asthma exacerbations, with the monthly exacerbations rate remaining the same throughout the year.<a href="#bib46" class="elsevierStyleCrossRefs">23</a> Our study seems to support these results, as no pattern of seasonal asthma exacerbations was evident throughout the year in these patients treated with omalizumab.The reduction of OCS intake shown in this study is in accordance with previous reports.<a href="#bib30" class="elsevierStyleCrossRefs">7</a>, <a href="#bib31" class="elsevierStyleCrossRefs">8</a>, <a href="#bib35" class="elsevierStyleCrossRefs">12</a>, <a href="#bib41" class="elsevierStyleCrossRefs">18</a>Our study was the first multicentre real-life study on the effect of omalizumab in patients with severe persistent allergic asthma in Portugal. This study has several limitations. Firstly, at enrolment, patients were already using omalizumab as add-on therapy and no comparable prior data were available. Moreover, in one-third of the patients it was not possible to access the registries for the complete 12-month treatment period.<a name="sec0065" class="elsevierStyleCrossRefs"></a>ConclusionsThis multicentre study showed that Portuguese adult patients with severe persistent allergic asthma under treatment with omalizumab, achieved asthma control in 34% of the medical visits with only 1/3 requiring unscheduled or Emergency Room care because of asthma exacerbations, supporting the maintenance of the clinical effect during treatment with omalizumab in real life. Further prospective studies in real-life Portuguese settings are needed to assess the reduction in corticosteroids intake in patients starting omalizumab therapy. These studies should be useful for a grounded pharmacoeconomic evaluation of omalizumab treatment in Portugal.<a name="sec0070" class="elsevierStyleCrossRefs"></a>Ethical disclosures<a name="sec0075" class="elsevierStyleCrossRefs"></a>Protection of human and animal subjectsThe authors declare that no experiments were performed on humans or animals for this study.<a name="sec0080" class="elsevierStyleCrossRefs"></a>Confidentiality of dataThe authors declare that they have followed the protocols of their work centre 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.<a name="sec0085" class="elsevierStyleCrossRefs"></a>Right to privacy and informed consentThe 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.<a name="sec0090" class="elsevierStyleCrossRefs"></a>Conflict of interestThe authors declare that they have no conflict of interest.AcknowledgementsWe thank all members of the REAG (Rede de Especialistas em Asma Grave) specially Laura Simão, Aurora Carvalho, José Ferreira, Rui Silva, António Costa, António Antunes, Eugénia Almeida, Isabel Pereira and Luísa Barata who actively participated in study set-up and discussion of results. We also thank Ângela Lopes for data insertion and Orquídea Ribeiro, from the Biostatistical consulting team from CIDES (Health Information and Decision Sciences Department), for the support in data analysis. Finally we thank Novartis for an unrestricted grant that supported data processing and analysis.<a name="sec0095" class="elsevierStyleCrossRefs"></a>Appendix A. Supplementary materialSupplementary material associated with this article can be found in the online version available at doi:10.1016/j.rppnen.2015.03.002.<a name="sec0100" class="elsevierStyleCrossRefs"></a>Appendix A. Supplementary materialThe following are the supplementary material to this article:<elsevierMultimedia href="320v21n06-90445971mmc1.docx"></elsevierMultimedia><elsevierMultimedia href="320v21n06-90445971mmc2.docx"></elsevierMultimedia>Received 30 October 2014 Accepted 8 March 2015 Corresponding author. fonseca.ja@gmail.com" "pdfFichero" => "320v21n06a90445971pdf001.pdf" "tienePdf" => true "PalabrasClave" => array:1 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec640966" "palabras" => array:5 [ 0 => "Severe asthma" 1 => "Omalizumab" 2 => "Asthma control" 3 => "Exacerbations" 4 => "Observational study" ] ] ] ] "tieneResumen" => true "resumen" => array:1 [ "en" => array:1 [ "resumen" => "The analysis of outcomes from patients with severe asthma treated with omalizumab, using real-life prospective data, should contribute to future informed decisions about this treatment in Portugal.The aim of this study was to assess the clinical effect of omalizumab in Portuguese patients with severe persistent allergic asthma, considering specifically asthma control and exacerbations.This was an observational, prospective, multicentre study. Data were collected at routine care over a 12-month period. Disease control was defined by Control of Allergic Rhinitis and Asthma Test (CARAT) global score >24.All asthma patients already under treatment with omalizumab in 7 departments from 6 Portuguese hospitals were included (n = 48). Most (77%) patients were female and the mean (SD) age was 51.9 (10.2) years old. During the study period, asthma was controlled in 34% of the visits and the 12-month exacerbation rate was 1.7 per patient (0.6 with unscheduled medical care). One-third of the patients needed unscheduled medical care because of asthma and 29% had to start or increase oral corticosteroid. There was still a 41% reduction in the total sum of oral corticosteroids usage from the first to the last trimester of the study.During routine treatment with omalizumab, Portuguese patients with severe asthma achieved asthma control in 1/3 of the visits and only 1/3 needed unscheduled or Emergency Room care because of asthma exacerbations. These outcomes support the maintenance of the clinical effect during treatment with omalizumab in routine care in Portugal." ] ] "multimedia" => array:8 [ 0 => array:8 [ "identificador" => "fig1" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "copyright" => "Elsevier España" "figura" => array:1 [ 0 => array:4 [ "imagen" => "320v21n06-90445971fig1.jpg" "Alto" => 2290 "Ancho" => 3005 "Tamanyo" => 247025 ] ] "descripcion" => array:1 [ "en" => "Distribution of the number of exacerbations (A) unscheduled healthcare utilization (B) and increases in OCS intake (C) in the 12-month follow-up period." ] ] 1 => array:8 [ "identificador" => "fig2" "etiqueta" => "Figure 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "copyright" => "Elsevier España" "figura" => array:1 [ 0 => array:4 [ "imagen" => "320v21n06-90445971fig2.jpg" "Alto" => 4078 "Ancho" => 3034 "Tamanyo" => 673171 ] ] "descripcion" => array:1 [ "en" => "(A) Percentage of visits reporting controlled asthma and exacerbations according to the month of the year (all patients included). (B) Reports of controlled asthma and exacerbations during follow-up, per patient. In (B) numbers on the right indicate total months of follow-up; continuous grey lines represent the follow-up period and dashed grey lines interruptions in omalizumab treatment; red dots represent visits with report of exacerbation and blue dashes visits with CARAT global score >24¿data from the 20 patients treated with omalizumab in Centro Hospitalar São João, EPE." ] ] 2 => array:8 [ "identificador" => "fig3" "etiqueta" => "Figure 3" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "copyright" => "Elsevier España" "figura" => array:1 [ 0 => array:4 [ "imagen" => "320v21n06-90445971fig3.jpg" "Alto" => 2181 "Ancho" => 2740 "Tamanyo" => 353190 ] ] "descripcion" => array:1 [ "en" => "Mean dosage of oral corticosteroids intake in the first and last trimester of the follow-up year (considering the 13 patients with OCS intake), (A) Overall reduction (B) Per patient. In (B) arrows represent the dose variation from the first to the last trimester; red lines represent increases and blue lines decrease in the dosage of oral corticosteroid intake; and dots represent no variation in the dosage." ] ] 3 => array:6 [ "identificador" => "fig4" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "copyright" => "Elsevier España" "descripcion" => array:1 [ "en" => "Distribution of the number of exacerbations (A) unscheduled healthcare utilization (B) and increases in OCS intake (C) in the 12-month follow-up period." ] ] 4 => array:6 [ "identificador" => "fig5" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "copyright" => "Elsevier España" "descripcion" => array:1 [ "en" => "(A) Percentage of visits reporting controlled asthma and exacerbations according to the month of the year (all patients included). (B) Reports of controlled asthma and exacerbations during follow-up, per patient. In (B) numbers on the right indicate total months of follow-up; continuous grey lines represent the follow-up period and dashed grey lines interruptions in omalizumab treatment; red dots represent visits with report of exacerbation and blue dashes visits with CARAT global score >24–data from the 20 patients treated with omalizumab in Centro Hospitalar São João, EPE." ] ] 5 => array:6 [ "identificador" => "fig6" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "copyright" => "Elsevier España" "descripcion" => array:1 [ "en" => "Mean dosage of oral corticosteroids intake in the first and last trimester of the follow-up year (considering the 13 patients with OCS intake), (A) Overall reduction (B) Per patient. In (B) arrows represent the dose variation from the first to the last trimester; red lines represent increases and blue lines decrease in the dosage of oral corticosteroid intake; and dots represent no variation in the dosage." ] ] 6 => array:6 [ "identificador" => "mmc1" "tipo" => "MULTIMEDIAECOMPONENTE" "mostrarFloat" => true "mostrarDisplay" => false "copyright" => "Elsevier España" "Ecomponente" => array:2 [ "fichero" => "320v21n06-90445971mmc1.docx" "ficheroTamanyo" => 20151 ] ] 7 => array:6 [ "identificador" => "mmc2" "tipo" => "MULTIMEDIAECOMPONENTE" "mostrarFloat" => true "mostrarDisplay" => false "copyright" => "Elsevier España" "Ecomponente" => array:2 [ "fichero" => "320v21n06-90445971mmc2.docx" "ficheroTamanyo" => 20686 ] ] ] "bibliografia" => array:2 [ "titulo" => "Bibliography" "seccion" => array:1 [ 0 => array:1 [ "bibliografiaReferencia" => array:23 [ 0 => array:3 [ "identificador" => "bib24" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma. 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A.S.. Sousaa, A.M.. Pereirab,c,d, J.A.. Fonsecaa,

,c,d, L.F.. Azevedoa,d, C.. Abreue, A.. Arrobasf, T.. Calvog, M.J.. Silvestreg, L.. Cunhah, H.. Falcãoh, M.. Drummondi, L.. Geraldesj, C.. Loureirok

a Center for Research in Health Technologies and Information Systems, Faculdade de Medicina da Universidade do Porto, Porto, Portugal

b Allergy Department, Centro Hospitalar de São João, EPE, Porto, Portugal

c Allergy Unit, CUF Porto Instituto e CUF Porto Hospital, Portugal

d Health Information and Decision Sciences Department, Faculdade de Medicina da Universidade do Porto, Porto, Portugal

e Allergy Department, Hospital Pedro Hispano Unidade Local de Saúde de Matosinhos, EPE, Matosinhos, Portugal

f Pulmonology Department, Hospital Geral de Coimbra Centro Hospitalar e Universitário de Coimbra, EPE, Coimbra, Portugal

g Pulmonology Department, Centro Hospitalar de Trás os Montes e Alto Douro, EPE, Vila Real, Portugal

h Allergy Department, Centro Hospitalar do Porto, EPE, Porto, Portugal

i Pulmonology Department, Centro Hospitalar de São João, EPE, Porto, Portugal

j Allergy Department, Centro Hospitalar do Alto Ave, EPE, Guimarães, Portugal

k Pulmonology Department, Centro Hospitalar e Universitário de Coimbra, EPE, Coimbra, Portugal

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    "textoCompleto" => "<a name="sec0005" class="elsevierStyleCrossRefs"></a><span class="elsevierStyleSectionTitle">Introduction</span><p class="elsevierStylePara">Severe asthma was recently defined by the European Respiratory Society&#47;American Thoracic Society as &#8220;asthma which requires treatment with high dose inhaled corticosteroids plus a second controller &#40;and&#47;or systemic corticosteroids&#41; to prevent it from becoming &#8216;uncontrolled&#8217; or asthma which remains &#8216;uncontrolled&#8217; despite this therapy&#8221;&#46;<a href="&#35;bib24" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">1</span></a> It is estimated that up to 15&#37; of asthma patients may have severe asthma&#46;<a href="&#35;bib25" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">2</span></a> These few patients account for a disproportionate part of the burden and healthcare costs associated with asthma&#46;<a href="&#35;bib26" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">3</span></a></p><p class="elsevierStylePara">Omalizumab is a humanized anti-IgE antibody recommended for treating severe allergic IgE-mediated persistent asthma as an add-on to optimized standard therapy in people aged 6 years or older who need continuous or frequent treatment with oral corticosteroids &#40;OCS&#41; &#40;defined as 4 or more courses in the previous year&#41;&#46;<a href="&#35;bib27" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">4</span></a> Previous studies in adults have shown that treatment with omalizumab is associated with an improvement in the control of asthma symptoms&#44; with decreased frequency and use of rescue medication and OCS&#44; and with a reduction in the total asthma-related emergency visits &#40;including hospital admissions&#44; emergency department visits and unscheduled visits to the doctor&#41;&#46;<a href="&#35;bib27" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">4</span></a> However&#44; most of these data come from clinical trials&#44; primarily designed to assess treatment efficacy in highly selected patients&#59; this poses problems when generalizing to daily clinical practice&#46; Real-life prospective studies&#44; presented as a pragmatic approach to everyday clinical practice&#44; are fundamental to assess the impact of omalizumab treatment in patients with severe asthma and should contribute to future informed decisions about this treatment&#46; In Portugal&#44; although four studies described outcomes of omalizumab treatment in real-life settings&#44;<a href="&#35;bib28" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">5</span></a><span class="elsevierStyleSup">&#44; </span><a href="&#35;bib29" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">6</span></a><span class="elsevierStyleSup">&#44; </span><a href="&#35;bib30" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">7</span></a><span class="elsevierStyleSup">&#44; </span><a href="&#35;bib31" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">8</span></a> only one is prospective and it was conducted in a single healthcare unit&#46;</p><p class="elsevierStylePara">The aim of this prospective multicentre study was to assess the clinical effect of omalizumab in Portuguese patients with severe persistent allergic asthma&#44; specifically concerning asthma control and exacerbations&#46;</p><a name="sec0010" class="elsevierStyleCrossRefs"></a><span class="elsevierStyleSectionTitle">Methods</span><a name="sec0015" class="elsevierStyleCrossRefs"></a><span class="elsevierStyleSectionTitle">Design</span><p class="elsevierStylePara">This was a multicentre&#44; descriptive&#44; observational&#44; prospective study&#44; conducted during routine asthma care&#46; The target population was individuals treated with omalizumab for severe persistent asthma&#46;</p><a name="sec0020" class="elsevierStyleCrossRefs"></a><span class="elsevierStyleSectionTitle">Setting and participants</span><p class="elsevierStylePara">The study was conducted in seven Pulmonology and Allergology departments from six hospitals in north and centre mainland Portugal&#46; In each unit&#44; all asthma patients under treatment with omalizumab were included&#44; regardless of the age&#44; length of previous therapy with omalizumab or actual treatment schedule&#46; All patients had omalizumab treatment approved by the therapeutic commission and hospital administration&#44; as required in Portuguese hospitals&#46; Minimal criteria for approval of omalizumab treatment for asthma are uncontrolled&#44; severe persistent&#44; allergic asthma&#44; with frequent exacerbations&#46;</p><a name="sec0025" class="elsevierStyleCrossRefs"></a><span class="elsevierStyleSectionTitle">Data collection</span><p class="elsevierStylePara">Data were collected at each routine visit for omalizumab administration&#44; during 12 consecutive months&#46; In the participating centres&#44; omalizumab was administered at 2- or 4-week intervals with doses based on IgE serum levels and body weight&#44; as recommended by EMEA &#8211; European Medicines Agency&#46;<a href="&#35;bib32" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">9</span></a> A structured form&#44; to be filled by both the patient and the nurse responsible for omalizumab administration&#44; was developed in order to standardize data collection at the different study sites&#46; This form included questions on asthma worsening&#44; medication intake&#44; healthcare resources utilization and work&#47;school absenteeism&#59; information on side effects was possibly related with the previous treatment administration&#46; The Control of Allergic Rhinitis and Asthma Test &#40;CARAT&#41;<a href="&#35;bib33" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">10</span></a><span class="elsevierStyleSup">&#44; </span><a href="&#35;bib34" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">11</span></a> was also part of the form&#46;</p><p class="elsevierStylePara">Data collection spanned from January 2011 to December 2013 in the different departments &#40;Additional file 1&#41;&#46;</p><a name="sec0030" class="elsevierStyleCrossRefs"></a><span class="elsevierStyleSectionTitle">Outcomes</span><p class="elsevierStylePara"><span class="elsevierStyleItalic">Asthma and rhinitis control</span> was defined by CARAT global score &#62;24&#46; CARAT lower airways score &#8805;16 and upper airways score &#62;8 were the cut-off values for control of&#44; respectively&#44; the lower and upper airways only&#46;</p><p class="elsevierStylePara"><span class="elsevierStyleItalic">Asthma exacerbation</span> was defined as having unscheduled healthcare utilization or increases in OCS intake because of asthma&#46; <span class="elsevierStyleItalic">Asthma worsening</span>&#44; <span class="elsevierStyleItalic">unscheduled healthcare utilization</span> and <span class="elsevierStyleItalic">increases in oral corticosteroid intake</span> were based on a positive answer to the questions&#58; &#8220;In the last 3 days&#44; have you felt your asthma getting worse&#63;&#8221;&#59; &#8220;Since the last administration&#44; have you had any unscheduled healthcare visit or emergency room visit because of your asthma&#63;&#8221; and &#8220;In the last 3 days&#44; did you need to start or increase oral corticosteroid intake&#63;&#8221;&#44; respectively&#46;</p><a name="sec0035" class="elsevierStyleCrossRefs"></a><span class="elsevierStyleSectionTitle">Statistical analysis</span><p class="elsevierStylePara">Statistical analyses were performed using IBM SPSS Statistics version 21 &#40;2012 SPSS Inc&#46;&#44; IBM Company&#44; Chicago&#44; US&#41;&#46; Categorical and continuous variables were analyzed using descriptive statistics as appropriate&#46; Survival analysis was used to assess the time until the first exacerbation&#46; Generalized Estimating Equations&#44; taking into account the multiple measurements in this longitudinal design&#44; were used to assess variations in control scores over time&#59; a Wald Chi-square test with a <span class="elsevierStyleItalic">p</span>-value of &#60;0&#46;05 was considered statistically significant&#46; As CARAT evaluates a 4-week period&#44; control scores were analyzed for visits with at least a 4-week interval&#46;</p><a name="sec0040" class="elsevierStyleCrossRefs"></a><span class="elsevierStyleSectionTitle">Results</span><p class="elsevierStylePara">A total of 48 adults with severe persistent allergic asthma were included &#40;<a href="&#35;t0005" class="elsevierStyleCrossRefs">Table 1</a>&#41;&#46; Patients were under treatment with omalizumab for between 0 and 67 months&#44; most for more than 3 years &#40;median&#44; 45 months&#41;&#46; Most patients &#40;<span class="elsevierStyleItalic">n</span>&#160;&#61;&#160;31&#44; 65&#37;&#41; were prospectively followed for 12 months and five were followed for less than 9 months &#40;Additional file 1&#41;&#46; During the study&#44; the median &#40;min&#8211;max&#41; number of medical visits for each patient was 14 &#40;7&#8211;28&#41;&#46; Side effects were reported in 5&#37; of the visits &#40;Additional file 2&#41;&#59; thirty-two &#40;67&#37;&#41; patients did not report any side effect during the study&#46;</p><p class="elsevierStylePara">Table 1&#46; Characteristics of the study population &#40;<span class="elsevierStyleItalic">n</span>&#160;&#61;&#160;48&#41;&#46;</p><a name="t0005" class="elsevierStyleCrossRefs"></a><p class="elsevierStylePara"></p><table><tr align="left"><td><span class="elsevierStyleItalic">Female &#40;n&#44; &#37;&#41;</span></td><td>36</td><td>77</td></tr><tr align="left"><td colspan="3">&#160;</td></tr><tr align="left"><td><span class="elsevierStyleItalic">Age &#40;mean&#44; SD&#41;</span></td><td>52</td><td>10</td></tr><tr align="left"><td colspan="3">&#160;</td></tr><tr align="left"><td colspan="3"><span class="elsevierStyleItalic">Hospital units &#40;n&#44; &#37;&#41;</span></td></tr><tr align="left"><td>Centro Hospitalar e Universit&#225;rio de Coimbra&#44; EPE &#8211; Pulmonology</td><td>15</td><td>31</td></tr><tr align="left"><td>Centro Hospitalar S&#227;o Jo&#227;o&#44; EPE &#8211; Allergology</td><td>12</td><td>39</td></tr><tr align="left"><td>Centro Hospitalar S&#227;o Jo&#227;o&#44; EPE &#8211; Pulmonology</td><td>8</td><td>26</td></tr><tr align="left"><td>Centro Hospitalar do Porto &#8211; Allergology</td><td>6</td><td>13</td></tr><tr align="left"><td>Centro Hospitalar de Tr&#225;s-os-Montes e Alto Douro &#8211; Pulmonology</td><td>4</td><td>8</td></tr><tr align="left"><td>Hospital Pedro Hispano &#8211; Allergology</td><td>2</td><td>4</td></tr><tr align="left"><td>Centro Hospitalar do Alto Ave &#8211; Allergology</td><td>1</td><td>2</td></tr><tr align="left"><td colspan="3">&#160;</td></tr><tr align="left"><td><span class="elsevierStyleItalic">Follow-up period&#44; months &#40;median&#44; min</span>&#8211;<span class="elsevierStyleItalic">max&#41;</span></td><td>12</td><td>3&#8211;12</td></tr><tr align="left"><td colspan="3">&#160;</td></tr><tr align="left"><td><span class="elsevierStyleItalic">Visits with reported OCS intake &#40;mean&#37; per patient&#44; SD&#41;</span></td><td>15</td><td>32</td></tr></table><p class="elsevierStylePara">SD &#8211; standard deviation&#59; OCS &#8211; oral corticosteroid&#46;<br></br></p><a name="sec0045" class="elsevierStyleCrossRefs"></a><span class="elsevierStyleSectionTitle">Asthma control</span><p class="elsevierStylePara">CARAT scores were analyzed for visits with at least a 4-week interval in a total of 414 visits&#46; During the study period&#44; asthma was controlled in 34&#37; of the visits&#59; the mean &#40;SD&#41; CARAT score was 20&#46;4 &#40;7&#46;5&#41;&#46; There was no statistically significant variation in any of the CARAT mean scores during the 12-month follow-up period &#40;<span class="elsevierStyleItalic">p</span>&#160;&#62;&#160;0&#46;05&#41;&#46;</p><a name="sec0050" class="elsevierStyleCrossRefs"></a><span class="elsevierStyleSectionTitle">Asthma exacerbations</span><p class="elsevierStylePara">During follow-up&#44; 26 patients &#40;54&#37;&#41; had at least one asthma exacerbation &#40;<a href="&#35;f0005" class="elsevierStyleCrossRefs">Figure 1</a>&#41;&#59; the 12-month rate of asthma exacerbations per patient was 1&#46;7&#8211;1&#46;3 increases with OCS intake and 0&#46;6 unscheduled healthcare utilizations&#46; The first exacerbation occurred on average &#40;mean &#91;95&#37; CI&#93;&#41; 7&#46;2 &#40;5&#46;9&#8211;8&#46;6&#41; months after entering the study&#46; There was no clear pattern of distribution of asthma exacerbations and control throughout the year &#40;<a href="&#35;f0010" class="elsevierStyleCrossRefs">Figure 2</a>&#41;&#46;</p><a name="f0005" class="elsevierStyleCrossRefs"></a><p class="elsevierStylePara"><img src="320v21n06-90445971fig1.jpg" alt="Distribution of the number of exacerbations &#40;A&#41; unscheduled healthcare utilization &#40;B&#41; and increases in OCS intake &#40;C&#41; in the 12-month follow-up period&#46;"></img></p><p class="elsevierStylePara">Figure 1&#46; Distribution of the number of exacerbations &#40;A&#41; unscheduled healthcare utilization &#40;B&#41; and increases in OCS intake &#40;C&#41; in the 12-month follow-up period&#46;</p><a name="f0010" class="elsevierStyleCrossRefs"></a><p class="elsevierStylePara"><img src="320v21n06-90445971fig2.jpg" alt="&#40;A&#41; Percentage of visits reporting controlled asthma and exacerbations according to the month of the year &#40;all patients included&#41;&#46; &#40;B&#41; Reports of controlled asthma and exacerbations during follow-up&#44; per patient&#46; In &#40;B&#41; numbers on the right indicate total months of follow-up&#59; continuous grey lines represent the follow-up period and dashed grey lines interruptions in omalizumab treatment&#59; red dots represent visits with report of exacerbation and blue dashes visits with CARAT global score &#62;24&#8211;data from the 20 patients treated with omalizumab in Centro Hospitalar S&#227;o Jo&#227;o&#44; EPE&#46;"></img></p><p class="elsevierStylePara">Figure 2&#46; &#40;A&#41; Percentage of visits reporting controlled asthma and exacerbations according to the month of the year &#40;all patients included&#41;&#46; &#40;B&#41; Reports of controlled asthma and exacerbations during follow-up&#44; per patient&#46; In &#40;B&#41; numbers on the right indicate total months of follow-up&#59; continuous grey lines represent the follow-up period and dashed grey lines interruptions in omalizumab treatment&#59; red dots represent visits with report of exacerbation and blue dashes visits with CARAT global score &#62;24&#8211;data from the 20 patients treated with omalizumab in Centro Hospitalar S&#227;o Jo&#227;o&#44; EPE&#46;</p><p class="elsevierStylePara">Thirty-three &#40;69&#37;&#41; participants reported at least one period of worsening of asthma symptoms without needing unscheduled medical care or OCS intake&#46; Eight &#40;17&#37;&#41; had more than four periods of worsening of asthma&#46;</p><a name="sec0055" class="elsevierStyleCrossRefs"></a><span class="elsevierStyleSectionTitle">Oral corticosteroids intake</span><p class="elsevierStylePara">Fourteen patients &#40;29&#37;&#41; took OCS because of asthma at least once during the follow-up&#46; Seven patients were taking daily OCS in the first visit and five of them took OCS during the full length of the study&#44; in a mean &#40;SD&#41; dosage of 18&#46;9 &#40;4&#46;4&#41;&#160;mg prednisolone&#47;day&#46; Comparing the first and the last trimesters of the study&#44; seven patients reduced the daily dosage of OCS&#44; four patients reported a dosage increase&#44; and two had no variation&#46; Overall&#44; the daily dosage of OCS had a non-significant reduction of 41&#46;6&#37; &#40;<a href="&#35;f0015" class="elsevierStyleCrossRefs">Figure 3</a>&#41;&#46; One patient had a follow-up inferior to two trimesters and was not considered for comparison purposes&#46;</p><a name="f0015" class="elsevierStyleCrossRefs"></a><p class="elsevierStylePara"><img src="320v21n06-90445971fig3.jpg" alt="Mean dosage of oral corticosteroids intake in the first and last trimester of the follow-up year &#40;considering the 13 patients with OCS intake&#41;&#44; &#40;A&#41; Overall reduction &#40;B&#41; Per patient&#46; In &#40;B&#41; arrows represent the dose variation from the first to the last trimester&#59; red lines represent increases and blue lines decrease in the dosage of oral corticosteroid intake&#59; and dots represent no variation in the dosage&#46;"></img></p><p class="elsevierStylePara">Figure 3&#46; Mean dosage of oral corticosteroids intake in the first and last trimester of the follow-up year &#40;considering the 13 patients with OCS intake&#41;&#44; &#40;A&#41; Overall reduction &#40;B&#41; Per patient&#46; In &#40;B&#41; arrows represent the dose variation from the first to the last trimester&#59; red lines represent increases and blue lines decrease in the dosage of oral corticosteroid intake&#59; and dots represent no variation in the dosage&#46;</p><a name="sec0060" class="elsevierStyleCrossRefs"></a><span class="elsevierStyleSectionTitle">Discussion</span><p class="elsevierStylePara">During the 12-month follow-up&#44; patients with severe persistent allergic asthma treated with omalizumab had their asthma controlled in 34&#37; of the visits&#59; 2&#47;3 had no need for unscheduled medical care due to asthma and 46&#37; remained exacerbation free&#46; The asthma exacerbation rate was 1&#46;7 exacerbations per patient per year &#40;the rate of treatment courses with OCS was 1&#46;3 and of unscheduled healthcare utilizations was 0&#46;6&#41;&#46;</p><p class="elsevierStylePara">Previously published observational studies performed in real-life settings reported that omalizumab is effective in the treatment of patients with severe persistent allergic asthma&#46;<a href="&#35;bib28" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">5</span></a><span class="elsevierStyleSup">&#44; </span><a href="&#35;bib35" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">12</span></a><span class="elsevierStyleSup">&#44; </span><a href="&#35;bib36" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">13</span></a><span class="elsevierStyleSup">&#44; </span><a href="&#35;bib37" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">14</span></a><span class="elsevierStyleSup">&#44; </span><a href="&#35;bib38" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">15</span></a><span class="elsevierStyleSup">&#44; </span><a href="&#35;bib39" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">16</span></a><span class="elsevierStyleSup">&#44; </span><a href="&#35;bib40" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">17</span></a><span class="elsevierStyleSup">&#44; </span><a href="&#35;bib41" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">18</span></a></p><p class="elsevierStylePara">The present study showed that the proportion of patients with good asthma control in these patients with severe persistent allergic asthma was stable&#46; The asthma control score did not change significantly during the follow-up period probably because patients were already under treatment with omalizumab at enrolment&#46; This &#8216;stability&#8217; concurs with several studies<a href="&#35;bib28" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">5</span></a><span class="elsevierStyleSup">&#44; </span><a href="&#35;bib39" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">16</span></a> that reported improvements in asthma control in the first 16 weeks of omalizumab treatment and a tendency to stabilize the effect in the following months&#46; Previously published studies using CARAT questionnaire to assess the control of asthma and rhinitis in other settings found a mean &#40;SD&#41; CARAT score of 17&#46;8 &#40;6&#46;4&#41; in a community of inner Portugal&#44;<a href="&#35;bib42" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">19</span></a> 17&#46;8 &#40;0&#46;2&#41; in patients followed in the Allergology Department of a University Hospital<a href="&#35;bib43" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">20</span></a> and 17&#46;2 &#40;6&#46;7&#41; in patients referred to the Allergy outpatient clinic from a district hospital&#46;<a href="&#35;bib44" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">21</span></a> The mean CARAT score found in the present study for patients with severe asthma is similar to those found in patients with non-severe asthma&#44; suggesting a positive effect of omalizumab treatment&#46;</p><p class="elsevierStylePara">The rate of 0&#46;6 emergency visits per patient-year observed in the present study is inferior to the rates reported by Molimard and co-workers &#8211; 1&#46;1 emergency visits per patient-year after a follow-up of more than 5 months&#44;<a href="&#35;bib41" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">18</span></a> and by Cazzola and co-workers &#8211; 1&#46;2 visits per patient-year after a follow-up of 12 months&#46;<a href="&#35;bib35" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">12</span></a></p><p class="elsevierStylePara">The exacerbation rate observed in the present study is lower than the rates reported in France<a href="&#35;bib41" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">18</span></a> and in the PERSIST study<a href="&#35;bib39" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">16</span></a> but greater than those of Germany&#44;<a href="&#35;bib40" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">17</span></a> Italy&#44;<a href="&#35;bib35" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">12</span></a> Ireland<a href="&#35;bib37" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">14</span></a> and Spain&#44;<a href="&#35;bib38" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">15</span></a> in similar studies&#46; Overall&#44; in our study&#44; the frequency of asthma exacerbations during one-year omalizumab treatment was lower than expected for these severe patients&#46;<a href="&#35;bib45" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">22</span></a> However&#44; in spite of being treated with omalizumab&#44; five patients had &#8805;5 exacerbations&#46; We could speculate whether before starting omalizumab the asthma control in these patients was even worse or if the treatment with omalizumab was ineffective and should be discontinued&#46;</p><p class="elsevierStylePara">Previous work found that omalizumab had a marked effect in the reduction of seasonal peaks of asthma exacerbations&#44; with the monthly exacerbations rate remaining the same throughout the year&#46;<a href="&#35;bib46" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">23</span></a> Our study seems to support these results&#44; as no pattern of seasonal asthma exacerbations was evident throughout the year in these patients treated with omalizumab&#46;</p><p class="elsevierStylePara">The reduction of OCS intake shown in this study is in accordance with previous reports&#46;<a href="&#35;bib30" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">7</span></a><span class="elsevierStyleSup">&#44; </span><a href="&#35;bib31" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">8</span></a><span class="elsevierStyleSup">&#44; </span><a href="&#35;bib35" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">12</span></a><span class="elsevierStyleSup">&#44; </span><a href="&#35;bib41" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">18</span></a></p><p class="elsevierStylePara">Our study was the first multicentre real-life study on the effect of omalizumab in patients with severe persistent allergic asthma in Portugal&#46; This study has several limitations&#46; Firstly&#44; at enrolment&#44; patients were already using omalizumab as add-on therapy and no comparable prior data were available&#46; Moreover&#44; in one-third of the patients it was not possible to access the registries for the complete 12-month treatment period&#46;</p><a name="sec0065" class="elsevierStyleCrossRefs"></a><span class="elsevierStyleSectionTitle">Conclusions</span><p class="elsevierStylePara">This multicentre study showed that Portuguese adult patients with severe persistent allergic asthma under treatment with omalizumab&#44; achieved asthma control in 34&#37; of the medical visits with only 1&#47;3 requiring unscheduled or Emergency Room care because of asthma exacerbations&#44; supporting the maintenance of the clinical effect during treatment with omalizumab in real life&#46; Further prospective studies in real-life Portuguese settings are needed to assess the reduction in corticosteroids intake in patients starting omalizumab therapy&#46; These studies should be useful for a grounded pharmacoeconomic evaluation of omalizumab treatment in Portugal&#46;</p><a name="sec0070" class="elsevierStyleCrossRefs"></a><span class="elsevierStyleSectionTitle">Ethical disclosures</span><a name="sec0075" class="elsevierStyleCrossRefs"></a><span class="elsevierStyleSectionTitle">Protection of human and animal subjects</span><p class="elsevierStylePara">The authors declare that no experiments were performed on humans or animals for this study&#46;</p><a name="sec0080" class="elsevierStyleCrossRefs"></a><span class="elsevierStyleSectionTitle">Confidentiality of data</span><p class="elsevierStylePara">The authors declare that they have followed the protocols of their work centre 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&#46;</p><a name="sec0085" class="elsevierStyleCrossRefs"></a><span class="elsevierStyleSectionTitle">Right to privacy and informed consent</span><p class="elsevierStylePara">The authors have obtained the written informed consent of the patients or subjects mentioned in the article&#46; The corresponding author is in possession of this document&#46;</p><a name="sec0090" class="elsevierStyleCrossRefs"></a><span class="elsevierStyleSectionTitle">Conflict of interest</span><p class="elsevierStylePara">The authors declare that they have no conflict of interest&#46;</p><p class="elsevierStylePara">Acknowledgements</p><p class="elsevierStylePara">We thank all members of the REAG &#40;Rede de Especialistas em Asma Grave&#41; specially Laura Sim&#227;o&#44; Aurora Carvalho&#44; Jos&#233; Ferreira&#44; Rui Silva&#44; Ant&#243;nio Costa&#44; Ant&#243;nio Antunes&#44; Eug&#233;nia Almeida&#44; Isabel Pereira and Lu&#237;sa Barata who actively participated in study set-up and discussion of results&#46; We also thank &#194;ngela Lopes for data insertion and Orqu&#237;dea Ribeiro&#44; from the Biostatistical consulting team from CIDES &#40;Health Information and Decision Sciences Department&#41;&#44; for the support in data analysis&#46; Finally we thank Novartis for an unrestricted grant that supported data processing and analysis&#46;</p><a name="sec0095" class="elsevierStyleCrossRefs"></a><span class="elsevierStyleSectionTitle">Appendix A&#46; Supplementary material</span><p class="elsevierStylePara">Supplementary material associated with this article can be found in the online version available at doi&#58;10&#46;1016&#47;j&#46;rppnen&#46;2015&#46;03&#46;002&#46;</p><a name="sec0100" class="elsevierStyleCrossRefs"></a><span class="elsevierStyleSectionTitle">Appendix A&#46; Supplementary material</span><p class="elsevierStylePara">The following are the supplementary material to this article&#58;</p><p class="elsevierStylePara"><elsevierMultimedia href="320v21n06-90445971mmc1.docx"></elsevierMultimedia></p><p class="elsevierStylePara"><elsevierMultimedia href="320v21n06-90445971mmc2.docx"></elsevierMultimedia></p><p class="elsevierStylePara">Received 30 October 2014 <br></br>Accepted 8 March 2015 </p><p class="elsevierStylePara">Corresponding author&#46; fonseca&#46;ja&#64;gmail&#46;com</p>"
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        "resumen" => "<p class="elsevierStylePara">The analysis of outcomes from patients with severe asthma treated with omalizumab&#44; using real-life prospective data&#44; should contribute to future informed decisions about this treatment in Portugal&#46;</p><p class="elsevierStylePara">The aim of this study was to assess the clinical effect of omalizumab in Portuguese patients with severe persistent allergic asthma&#44; considering specifically asthma control and exacerbations&#46;</p><p class="elsevierStylePara">This was an observational&#44; prospective&#44; multicentre study&#46; Data were collected at routine care over a 12-month period&#46; Disease control was defined by Control of Allergic Rhinitis and Asthma Test &#40;CARAT&#41; global score &#62;24&#46;</p><p class="elsevierStylePara">All asthma patients already under treatment with omalizumab in 7 departments from 6 Portuguese hospitals were included &#40;<span class="elsevierStyleItalic">n</span>&#160;&#61;&#160;48&#41;&#46; Most &#40;77&#37;&#41; patients were female and the mean &#40;SD&#41; age was 51&#46;9 &#40;10&#46;2&#41; years old&#46; During the study period&#44; asthma was controlled in 34&#37; of the visits and the 12-month exacerbation rate was 1&#46;7 per patient &#40;0&#46;6 with unscheduled medical care&#41;&#46; One-third of the patients needed unscheduled medical care because of asthma and 29&#37; had to start or increase oral corticosteroid&#46; There was still a 41&#37; reduction in the total sum of oral corticosteroids usage from the first to the last trimester of the study&#46;</p><p class="elsevierStylePara">During routine treatment with omalizumab&#44; Portuguese patients with severe asthma achieved asthma control in 1&#47;3 of the visits and only 1&#47;3 needed unscheduled or Emergency Room care because of asthma exacerbations&#46; These outcomes support the maintenance of the clinical effect during treatment with omalizumab in routine care in Portugal&#46;</p>"
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                            4 => "Gern JE"
                            5 => "Liu AH"
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                        "volumen" => "364"
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Article information

ISSN: 08732159
Original language: English

DOI:10.1016/j.rppnen.2015.03.002

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Year/Month	Html	Pdf	Total

2024 November	12	10	22
2024 October	63	42	105
2024 September	61	34	95
2024 August	79	47	126
2024 July	85	33	118
2024 June	82	40	122
2024 May	91	50	141
2024 April	71	37	108
2024 March	70	35	105
2024 February	49	31	80
2024 January	44	32	76
2023 December	46	22	68
2023 November	51	38	89
2023 October	61	38	99
2023 September	50	37	87
2023 August	66	20	86
2023 July	46	31	77
2023 June	67	17	84
2023 May	77	39	116
2023 April	59	22	81
2023 March	111	17	128
2023 February	84	25	109
2023 January	35	22	57
2022 December	71	15	86
2022 November	72	43	115
2022 October	66	29	95
2022 September	43	31	74
2022 August	50	37	87
2022 July	37	55	92
2022 June	41	28	69
2022 May	46	51	97
2022 April	53	44	97
2022 March	51	68	119
2022 February	40	44	84
2022 January	45	34	79
2021 December	43	38	81
2021 November	51	40	91
2021 October	47	44	91
2021 September	43	25	68
2021 August	33	23	56
2021 July	29	21	50
2021 June	41	25	66
2021 May	51	21	72
2021 April	145	68	213
2021 March	43	17	60
2021 February	48	15	63
2021 January	42	15	57
2020 December	47	14	61
2020 November	50	17	67
2020 October	44	28	72
2020 September	61	21	82
2020 August	90	30	120
2020 July	102	18	120
2020 June	101	24	125
2020 May	101	14	115
2020 April	102	9	111
2020 March	85	13	98
2020 February	109	31	140
2020 January	109	12	121
2019 December	103	23	126
2019 November	90	25	115
2019 October	92	20	112
2019 September	105	22	127
2019 August	333	23	356
2019 July	388	14	402
2019 June	414	11	425
2019 May	348	20	368
2019 April	340	34	374
2019 March	430	16	446
2019 February	402	5	407
2019 January	212	21	233
2018 December	114	8	122
2018 November	89	3	92
2018 October	119	8	127
2018 September	29	9	38
2018 August	39	21	60
2018 July	61	15	76
2018 June	68	15	83
2018 May	114	18	132
2018 April	85	22	107
2018 March	49	26	75
2018 February	30	10	40
2018 January	20	18	38
2017 December	29	20	49
2017 November	23	10	33
2017 October	22	19	41
2017 September	19	13	32
2017 August	22	21	43
2017 July	22	15	37
2017 June	14	13	27
2017 May	19	19	38
2017 April	10	4	14
2017 March	12	8	20
2017 February	8	6	14
2017 January	22	12	34
2016 December	21	8	29
2016 November	18	9	27
2016 October	39	8	47
2016 September	16	12	28
2016 August	25	22	47
2016 July	28	54	82
2016 June	1	99	100
2016 May	0	11	11
2016 April	22	1	23
2016 March	27	27	54
2016 February	88	54	142
2016 January	91	62	153
2015 December	88	80	168

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