Editorial
Augmentation Therapy Nowadays: Con
Terapia de aumento en la actualidad: con
Juan Bautista Gáldiz Iturri
Laboratorio Exploración Funcional, Servicio de Neumología, Hospital Universitario Cruces, CibeRes, Biocruces, Barakaldo, Spain
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=> "Gáldiz Iturri" "email" => array:1 [ 0 => "juanbautista.galdiziturri@osakidetza.net" ] ] ] "afiliaciones" => array:1 [ 0 => array:2 [ "entidad" => "Laboratorio Exploración Funcional, Servicio de Neumología, Hospital Universitario Cruces, CibeRes, Biocruces, Barakaldo, Spain" "identificador" => "aff0005" ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Terapia de aumento en la actualidad: con" ] ] "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall">Alpha-1 antitrypsin (A1AT) deficiency is a rare, incurable disease that is still underdiagnosed.<a class="elsevierStyleCrossRefs" href="#bib0080"><span class="elsevierStyleSup">1,2</span></a> The risk of developing symptoms depends on A1AT concentrations and other factors such as smoking or pollution. Approximately 60% of A1AT deficiency patients who present a PiZZ phenotype develop lung disease, and 2%–3% of cases of chronic obstructive pulmonary disease (COPD) are thought have this deficiency.<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">3</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">A relationship between the serum concentration of A1AT and the severity of emphysema (threshold of 11<span class="elsevierStyleHsp" style=""></span>μM/L) is assumed, and in theory, the administration of A1AT could prevent progression in patients with severe deficiencies.<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">4</span></a> Even so, the different reviews and studies have shown conflicting results.</p><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0005">Administration Schedules</span><p id="par0015" class="elsevierStylePara elsevierViewall">A1AT product information recommends weekly administration, which impacts greatly on the use of this treatment. Other regimens have been evaluated, including 3-weekly and monthly schedules, but studies have shown that the pharmacokinetic properties of A1AT administered in infusions of 120<span class="elsevierStyleHsp" style=""></span>mg/kg/14 days and 180<span class="elsevierStyleHsp" style=""></span>mg/kg/21 days do not achieve the same concentrations as weekly dosing.<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">5</span></a> Strictly speaking, this implies that dosing should be weekly, but this complicates treatment for a large number of potential patients, taking into account that it must be administered for life. The possibility of increasing the dose per kg and altering the frequency of administration is still being debated.</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Efficacy Variables</span><p id="par0020" class="elsevierStylePara elsevierViewall">Initially, the efficacy parameter evaluated was reduction in forced expiratory volume in 1<span class="elsevierStyleHsp" style=""></span>s (FEV1). Results were inconclusive and unsupported by evidence from randomized studies. The main reason for this lack of quality studies is the need to include large numbers of patients in order to detect changes in this variable − a difficult task in this disease.</p><p id="par0025" class="elsevierStylePara elsevierViewall">In the first randomized study, Dirksen et al.<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">6</span></a> assigned 56 patients with A1AT deficiency (Pi*ZZ) and FEV1 between 30% and 80% to receive A1AT 250<span class="elsevierStyleHsp" style=""></span>mg/kg or placebo for 3 years. The objective was to compare the rate of FEV1 reduction, but no significant differences were found between the groups. The mean annual rate of reduction in the placebo group was 25.2±22<span class="elsevierStyleHsp" style=""></span>ml vs 26.5±15.1<span class="elsevierStyleHsp" style=""></span>ml (<span class="elsevierStyleItalic">P</span>=0.96) in the treatment group, while no differences were found in variables such as diffusing capacity of the lung for carbon monoxide (DLCO). An analysis of patients included in a Spanish registry<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">7</span></a> revealed no differences in FEV1 progress between those who received or did not receive treatment, a result that the authors admitted was unexpected. This, and other studies with similar results, have led to a situation in which no single variable is currently used as a valid parameter.</p><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Lung Density</span><p id="par0030" class="elsevierStylePara elsevierViewall">The failure to prove FEV1 as a valid efficacy parameter prompted a search for other variables. In the above-mentioned study,<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">6</span></a> lung density measured by computed tomography (CT) was evaluated, revealing a non-significant trend (<span class="elsevierStyleItalic">P</span>=0.07) (2.6±0.41<span class="elsevierStyleHsp" style=""></span>g/l/year in the placebo group vs 1.5±0.41<span class="elsevierStyleHsp" style=""></span>g/l/year in the treatment group).</p><p id="par0035" class="elsevierStylePara elsevierViewall">The same authors presented data from the EXAcerbations and CT scan as Lung Endpoints (EXACTLE) study,<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">8</span></a> a pilot project designed to assess the effect of treatment on loss of lung density measured by CT and on the number of exacerbations. Seventy-seven patients were randomly assigned to weekly infusions of treatment or placebo for 2.5 years. There were significant trends in lung density in favor of the treatment group (the mean slope of change in 15th percentile lung density (PD15) was 0.857 [−0.065 to 1.778]; <span class="elsevierStyleItalic">P</span>=0.07). Again no differences were detected in loss of lung function as measured by FEV1, DLCO, and exacerbation rates between groups. A subsequent analysis of these data confirmed that PD15 is the most sensitive index of the progression of emphysema.<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">9</span></a> A comparison of various densitometry indexes indicated that the result was affected by the inspiratory volume at which the measurement (PD15) was obtained. The data from these 2 studies were pooled and reanalyzed,<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">10</span></a> and the mean average change from baseline in lung density was found to be −4.082<span class="elsevierStyleHsp" style=""></span>g/l for A1AT, and −6.379<span class="elsevierStyleHsp" style=""></span>g/l for placebo, with a significant difference in favor in the treatment group.</p><p id="par0040" class="elsevierStylePara elsevierViewall">Between 2006 and 2010, 180 patients with A1AT deficiency were randomized to receive replacement therapy (60<span class="elsevierStyleHsp" style=""></span>mg/kg) or placebo for 2 years in the RAPID-RCT study.<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">11</span></a> The annual rate of lung density loss at TLC alone was significantly less in patients in the treatment group (<span class="elsevierStyleItalic">n</span>=180; −1.45<span class="elsevierStyleHsp" style=""></span>g/l/year vs −2.19<span class="elsevierStyleHsp" style=""></span>g/l/year; <span class="elsevierStyleItalic">P</span>=0.017), but the same was not true of loss at FRC alone, while the annual rate of lung density loss at TLC and FRC combined did not differ between groups. This benefit was confirmed in the RAPID-OLE (open-label extension) study in which all patients received α1 proteinase inhibitor (A1PI). A similar study, the SPARTA trial, is currently ongoing.<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">12</span></a></p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Mortality</span><p id="par0045" class="elsevierStylePara elsevierViewall">Few research groups have investigated the impact of replacement therapy on mortality. A patient registry study<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">13</span></a> suggested that patients with FEV1 values <50% who received replacement therapy had greater survival than patients who did not. This study was not prospectively controlled to determine if the treatment was administered correctly, and uncontrolled factors between the treated and untreated groups may have confounded the findings.</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Exacerbations</span><p id="par0050" class="elsevierStylePara elsevierViewall">Neither of the studies mentioned above<a class="elsevierStyleCrossRefs" href="#bib0105"><span class="elsevierStyleSup">6,8</span></a> have shown any impact on exacerbation, and some commonly cited publications raise methodological concerns.<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">14</span></a></p><p id="par0055" class="elsevierStylePara elsevierViewall">Two Cochrane reviews, one recently completed,<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">15</span></a> conclude that there is insufficient evidence to recommend replacement therapy. In summary, the effectiveness of replacement therapy has generated controversy since it was first marketed. It is costly, inconvenient for the patient (weekly, intravenous, life-long), and the variables initially used for evaluation (FEV1, exacerbations) have been proven invalid. In recent years, CT (PD15) has emerged as a useful tool for determining effectiveness, and results, which appear promising, remain to be confirmed in ongoing studies (SPARTA). Even so, we must not ignore the fact that to measure this parameter, certain technology (CT, software) is required that is unavailable in most hospitals.</p></span></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:3 [ 0 => array:2 [ "identificador" => "sec0005" "titulo" => "Administration Schedules" ] 1 => array:3 [ "identificador" => "sec0010" "titulo" => "Efficacy Variables" "secciones" => array:3 [ 0 => array:2 [ "identificador" => "sec0015" "titulo" => "Lung Density" ] 1 => array:2 [ "identificador" => "sec0020" "titulo" => "Mortality" ] 2 => array:2 [ "identificador" => "sec0025" "titulo" => "Exacerbations" ] ] ] 2 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as: Gáldiz Iturri J. Terapia de aumento en la actualidad: con. Arch Bronconeumol. 2018;54:361–362.</p>" ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0015" "bibliografiaReferencia" => array:15 [ 0 => array:3 [ "identificador" => "bib0080" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Detection of alpha-1 antitrypsin deficiency in the US" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "M. Campos" 1 => "D. Shmuels" 2 => "J. 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| Year/Month | Html | Total | |
|---|---|---|---|
| 2024 November | 5 | 1 | 6 |
| 2024 October | 38 | 16 | 54 |
| 2024 September | 52 | 14 | 66 |
| 2024 August | 67 | 33 | 100 |
| 2024 July | 51 | 22 | 73 |
| 2024 June | 42 | 20 | 62 |
| 2024 May | 70 | 30 | 100 |
| 2024 April | 32 | 25 | 57 |
| 2024 March | 36 | 19 | 55 |
| 2024 February | 34 | 15 | 49 |
| 2023 March | 10 | 6 | 16 |
| 2023 February | 50 | 25 | 75 |
| 2023 January | 29 | 30 | 59 |
| 2022 December | 55 | 40 | 95 |
| 2022 November | 73 | 23 | 96 |
| 2022 October | 55 | 39 | 94 |
| 2022 September | 37 | 34 | 71 |
| 2022 August | 34 | 46 | 80 |
| 2022 July | 31 | 53 | 84 |
| 2022 June | 26 | 39 | 65 |
| 2022 May | 35 | 35 | 70 |
| 2022 April | 28 | 20 | 48 |
| 2022 March | 51 | 45 | 96 |
| 2022 February | 65 | 31 | 96 |
| 2022 January | 33 | 43 | 76 |
| 2021 December | 55 | 47 | 102 |
| 2021 November | 33 | 38 | 71 |
| 2021 October | 37 | 62 | 99 |
| 2021 September | 34 | 53 | 87 |
| 2021 August | 34 | 44 | 78 |
| 2021 July | 33 | 26 | 59 |
| 2021 June | 30 | 50 | 80 |
| 2021 May | 41 | 46 | 87 |
| 2021 April | 76 | 96 | 172 |
| 2021 March | 72 | 23 | 95 |
| 2021 February | 30 | 26 | 56 |
| 2021 January | 33 | 20 | 53 |
| 2020 December | 39 | 37 | 76 |
| 2020 November | 26 | 34 | 60 |
| 2020 October | 25 | 38 | 63 |
| 2020 September | 25 | 21 | 46 |
| 2020 August | 22 | 18 | 40 |
| 2020 July | 22 | 33 | 55 |
| 2020 March | 20 | 5 | 25 |
| 2020 February | 45 | 15 | 60 |
| 2020 January | 41 | 15 | 56 |
| 2019 December | 19 | 18 | 37 |
| 2019 November | 22 | 20 | 42 |
| 2019 October | 16 | 17 | 33 |
| 2019 September | 20 | 4 | 24 |
| 2019 August | 19 | 12 | 31 |
| 2019 July | 19 | 15 | 34 |
| 2019 June | 27 | 6 | 33 |
| 2019 May | 36 | 17 | 53 |
| 2019 April | 43 | 34 | 77 |
| 2019 March | 48 | 26 | 74 |
| 2019 February | 32 | 24 | 56 |
| 2019 January | 21 | 13 | 34 |
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