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array:23 [ "pii" => "S0025775324001933" "issn" => "00257753" "doi" => "10.1016/j.medcli.2024.01.045" "estado" => "S300" "fechaPublicacion" => "2024-08-30" "aid" => "6623" "copyright" => "Elsevier España, S.L.U.. All rights reserved" "copyrightAnyo" => "2024" "documento" => "article" "crossmark" => 1 "subdocumento" => "rev" "cita" => "Med Clin. 2024;163:189-98" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:1 [ "total" => 0 ] "itemSiguiente" => array:19 [ "pii" => "S0025775324001969" "issn" => "00257753" "doi" => "10.1016/j.medcli.2024.01.048" "estado" => "S300" "fechaPublicacion" => "2024-08-30" "aid" => "6626" "copyright" => "Elsevier España, S.L.U." 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En el cruce arteriovenoso donde se produce la ORVR, la arteria ateromatosa más rígida comprime la vena y se produce cambio en flujo venoso, lesión endotelial e hipercoagulabilidad, basado en la triada clásica de Virchow.</p>" ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "María Larrousse Morellón, Yéssica López Loureiro, Susana Ruiz Bilbao" "autores" => array:3 [ 0 => array:2 [ "nombre" => "María" "apellidos" => "Larrousse Morellón" ] 1 => array:2 [ "nombre" => "Yéssica" "apellidos" => "López Loureiro" ] 2 => array:2 [ "nombre" => "Susana" "apellidos" => "Ruiz Bilbao" ] ] ] ] ] "idiomaDefecto" => "es" "Traduccion" => array:1 [ "en" => array:9 [ "pii" => "S2387020624003371" "doi" => "10.1016/j.medcle.2024.07.003" "estado" => "S300" "subdocumento" => "" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:1 [ "total" => 0 ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2387020624003371?idApp=UINPBA00004N" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0025775324001969?idApp=UINPBA00004N" "url" => "/00257753/0000016300000004/v1_202408190637/S0025775324001969/v1_202408190637/es/main.assets" ] "itemAnterior" => array:19 [ "pii" => "S0025775324001854" "issn" => "00257753" "doi" => "10.1016/j.medcli.2024.01.039" "estado" => "S300" "fechaPublicacion" => "2024-08-30" "aid" => "6615" "copyright" => "Elsevier España, S.L.U." 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"Traduccion" => array:1 [ "en" => array:9 [ "pii" => "S2387020624003346" "doi" => "10.1016/j.medcle.2024.01.037" "estado" => "S300" "subdocumento" => "" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:1 [ "total" => 0 ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2387020624003346?idApp=UINPBA00004N" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0025775324001854?idApp=UINPBA00004N" "url" => "/00257753/0000016300000004/v1_202408190637/S0025775324001854/v1_202408190637/es/main.assets" ] "en" => array:19 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Review</span>" "titulo" => "Invasive aspergillosis: A comprehensive review" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "189" "paginaFinal" => "198" ] ] "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "Marina Machado, Jesús Fortún, Patricia Muñoz" "autores" => array:3 [ 0 => array:4 [ "nombre" => "Marina" "apellidos" => "Machado" "email" => array:1 [ 0 => "marina.machado@salud.madrid.org" ] "referencia" => array:4 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0010" ] 2 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">d</span>" "identificador" => "aff0020" ] 3 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">*</span>" "identificador" => "cor0005" ] ] ] 1 => array:3 [ "nombre" => "Jesús" "apellidos" => "Fortún" "referencia" => array:4 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">c</span>" "identificador" => "aff0015" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">d</span>" "identificador" => "aff0020" ] 2 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">e</span>" "identificador" => "aff0025" ] 3 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">f</span>" "identificador" => "aff0030" ] ] ] 2 => array:3 [ "nombre" => "Patricia" "apellidos" => "Muñoz" "referencia" => array:4 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0010" ] 2 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">g</span>" "identificador" => "aff0035" ] 3 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">h</span>" "identificador" => "aff0040" ] ] ] ] "afiliaciones" => array:8 [ 0 => array:3 [ "entidad" => "Clinical Microbiology and Infectious Diseases Department, Hospital General Universitario Gregorio Marañón, Madrid, Spain" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain" "etiqueta" => "b" "identificador" => "aff0010" ] 2 => array:3 [ "entidad" => "Infectious Diseases Department, Hospital Ramón y Cajal, Madrid, Spain" "etiqueta" => "c" "identificador" => "aff0015" ] 3 => array:3 [ "entidad" => "Universidad de Alcalá, Escuela de Doctorado, Alcalá de Henares, Spain" "etiqueta" => "d" "identificador" => "aff0020" ] 4 => array:3 [ "entidad" => "IRYCIS: Instituto Ramón y Cajal de Investigación Sanitaria, Madrid, Spain" "etiqueta" => "e" "identificador" => "aff0025" ] 5 => array:3 [ "entidad" => "CIBER de Enfermedades Infecciosas (CIBERINFEC), Madrid, Spain" "etiqueta" => "f" "identificador" => "aff0030" ] 6 => array:3 [ "entidad" => "CIBER de Enfermedades Respiratorias – CIBERES (CB06/06/0058), Madrid, Spain" "etiqueta" => "g" "identificador" => "aff0035" ] 7 => array:3 [ "entidad" => "Medicine Department, Faculty of Medicine, Universidad Complutense de Madrid, Spain" "etiqueta" => "h" "identificador" => "aff0040" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Aspergilosis invasiva: una revisión exhaustiva" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0010" "etiqueta" => "Fig. 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 1807 "Ancho" => 3341 "Tamanyo" => 607063 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Proposed flowchart of diagnosis and therapy in invasive aspergillosis.</p>" ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Aspergillosis is a fungal disease usually caused by <span class="elsevierStyleItalic">Aspergillus fumigatus</span> with a variety of clinical presentations depending on the immunologic status of the host. Those presentations are: hypersensitivity syndromes or allergic bronchopulmonary aspergillosis (ABPA), chronic pulmonary aspergillosis or semi-invasive forms, invasive airway forms, extrapulmonary and/or disseminated forms. Invasive forms will be the focus of this review.</p><p id="par0010" class="elsevierStylePara elsevierViewall">Invasive aspergillosis (IA) is an uncommon infection but with high mortality rate, particularly in immunocompromised patients. In recent years, this infection has undergone relevant changes with the emergence of new populations at risk, better diagnosis methods and therapeutic strategies.</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Aetiology</span><p id="par0015" class="elsevierStylePara elsevierViewall">IA is caused by a group of environmental moulds with universal distribution belonging to the genus <span class="elsevierStyleItalic">Aspergillus</span>. While hundreds of species are known, only a few are associated with human infections, primarily <span class="elsevierStyleItalic">A. fumigatus</span> followed by <span class="elsevierStyleItalic">Aspergillus flavus</span>, <span class="elsevierStyleItalic">Aspergillus niger</span>, and <span class="elsevierStyleItalic">Aspergillus terreus</span>.<a class="elsevierStyleCrossRef" href="#bib0305"><span class="elsevierStyleSup">1</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">Some species seem very similar or nearly identical in terms of their phenotype, but genetically distinct; these are defined as cryptic species. This genetic divergence becomes especially relevant in terms of resistance to antifungal treatment. Traditional methods may not be able to detect these species, emphasising the advanced techniques like DNA analysis to ensure accurate identification and effective aspergillosis management. In a multicentre surveillance study focusing on fungal diseases in Spain, 12% of all <span class="elsevierStyleItalic">Aspergillus</span> isolates were recognised as cryptic species.<a class="elsevierStyleCrossRef" href="#bib0310"><span class="elsevierStyleSup">2</span></a> Despite potentially increased triazole MICs in vitro, there is insufficient data regarding possible higher mortality rates in patients with cryptic species isolation.<a class="elsevierStyleCrossRef" href="#bib0315"><span class="elsevierStyleSup">3</span></a></p><p id="par0025" class="elsevierStylePara elsevierViewall">In the last two decades, different studies have reported an increasing prevalence of azole resistance in <span class="elsevierStyleItalic">Aspergillus</span>, not only in cryptic species but also in <span class="elsevierStyleItalic">A. fumigatus</span>-complex. The development of azole resistance in <span class="elsevierStyleItalic">A. fumigatus</span> is a worldwide concern, with a wide geographical variation from 0.2% to 14% of clinical samples and higher (up to 17%) in the environmental.<a class="elsevierStyleCrossRef" href="#bib0320"><span class="elsevierStyleSup">4</span></a> In a multicentre Spanish survey focused on <span class="elsevierStyleItalic">A. fumigatus</span> azole resistance, 847 isolates were collected from clinical samples of 29 hospitals between February and May 2019, regardless of their clinical significance. <span class="elsevierStyleItalic">A. fumigatus</span>-complex isolates showed a 7.4% rate of azole resistance, which is higher in cryptic species than in <span class="elsevierStyleItalic">A. fumigatus sensu-stricto</span> (95% vs. 5.5%), being the dominant mechanism of resistance the presence of TR34/L98H mutation of the gene encoding Cyp51A.<a class="elsevierStyleCrossRef" href="#bib0325"><span class="elsevierStyleSup">5</span></a> The pathogenesis of azole resistance is complex and multifactorial. Moreover, most of the studies have been conducted in <span class="elsevierStyleItalic">A. fumigatus</span>, and data are missing for other species. Although the origin of this mechanism of resistance is unclear, the TR34/L98H mutation is thought to be associated with environmental azole resistance, since the massive use of azole-based fungicides in agriculture could provoke cross-resistance with triazoles.<a class="elsevierStyleCrossRef" href="#bib0330"><span class="elsevierStyleSup">6</span></a> Such mutations have been described in azole-naïve patients and in those within long-term azole treatment, highlighting the complexity of the resistance mechanisms.<a class="elsevierStyleCrossRef" href="#bib0320"><span class="elsevierStyleSup">4</span></a></p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Pathogenesis and risk factors</span><p id="par0030" class="elsevierStylePara elsevierViewall">More than 60% of IA cases are caused by <span class="elsevierStyleItalic">A. fumigatus</span>, particularly in immunocompromised patients, due to its greater pathogenicity, invasive capacity and adaptability to different external conditions.</p><p id="par0035" class="elsevierStylePara elsevierViewall">Conidia of <span class="elsevierStyleItalic">Aspergillus</span> are wind-dispersed and can be present in the air, dust, food, air conditioning filters, and building construction, posing nosocomial risk factors for outbreaks, especially in immunocompromised patients.<a class="elsevierStyleCrossRef" href="#bib0335"><span class="elsevierStyleSup">7</span></a></p><p id="par0040" class="elsevierStylePara elsevierViewall">Aspergillosis typically results from inhaling conidia, primarily affecting the lungs and paranasal sinuses. The infection may localise at the entry site or spread contiguously or haematogenously, manifesting in different clinical forms, from asymptomatic colonisation to invasive infection. The combination of host and pathogen factors is crucial for aspergillosis development. The pulmonary system, constantly exposed to <span class="elsevierStyleItalic">Aspergillus</span> conidia, triggers a coordinated immune response for prompt elimination. Mucociliary clearance in the airways removes conidia, but impaired conditions like cystic fibrosis, may lead to colonisation or infection. Airway epithelial cells and alveolar macrophages serve as primary defenses against <span class="elsevierStyleItalic">Aspergillus</span>, with crucial macrophage receptors such as Dectin-1, DC-SIGN, and pentraxin 3 aiding conidia recognition. Neutrophils also play an important role, recognising <span class="elsevierStyleItalic">Aspergillus</span> similarly to alveolar macrophages, leading to the production of NADPH oxidase-induced reactive oxidant species (ROS) causing fungal cell death.<a class="elsevierStyleCrossRef" href="#bib0340"><span class="elsevierStyleSup">8</span></a></p><p id="par0045" class="elsevierStylePara elsevierViewall">IA predominantly affects immunosuppressed patients, depending on the severity of the immunosuppression. <a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a> describes, from highest to lowest risk, different immunosuppressed populations and situations that may lead to the development of aspergillosis.<a class="elsevierStyleCrossRef" href="#bib0305"><span class="elsevierStyleSup">1</span></a> Highest IA incidence rates occurs in chronic granulomatous disease (CGD) due to NADPH oxidase functional impairment, ranging from 26% to 45%.<a class="elsevierStyleCrossRef" href="#bib0345"><span class="elsevierStyleSup">9</span></a> These patients predominantly have pulmonary, osteomyelitis and focal brain infection.</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0050" class="elsevierStylePara elsevierViewall">Haematological malignancies and its intensive treatment (including transplantation) are also a very highly vulnerable population. Notably, acute myeloid leukaemia and its prolonged neutropenia during induction chemotherapy and allogeneic haematopoietic stem cell transplantation (HSCT) especially with graft-versus-host disease (GvHD) treated with corticosteroids and other immunotherapies. Recently, IA has been described in patient receiving chimeric antigen receptor T-cell therapy (CAR-T)<a class="elsevierStyleCrossRef" href="#bib0350"><span class="elsevierStyleSup">10</span></a> however, it was anecdotally reported with incidence rates ranged from 0.9% to 3.8%.<a class="elsevierStyleCrossRef" href="#bib0355"><span class="elsevierStyleSup">11</span></a> The severity of cytokine release syndrome (CRS) and the requirement of anti-IL-6 agents and corticosteroids were identified as risk factors for infection after CAR T-cell therapy. Onco-haematological therapy has undergone a significant revolution in recent years due to new targeted therapies associating different grades of immunosuppression and risk of infection. Cases of invasive fungal infections (IFI) have been described. For instance, in patients receiving Bruton's Tyrosine Kinase (BTK) Inhibitors, reported incidences range from 2.5% to 44%, with some cases with central nervous system (CNS) involvement.<a class="elsevierStyleCrossRef" href="#bib0360"><span class="elsevierStyleSup">12</span></a> Most of these patients were intensively pre-treated with different chemotherapy regimens as well as other immunotherapeutic agents.<a class="elsevierStyleCrossRef" href="#bib0365"><span class="elsevierStyleSup">13</span></a></p><p id="par0055" class="elsevierStylePara elsevierViewall">IA is also relatively common among patients undergoing solid organ transplantation (SOT),<a class="elsevierStyleCrossRef" href="#bib0370"><span class="elsevierStyleSup">14</span></a> with different incidences depending on the organ transplanted and the use of antifungal prophylaxis, ranging from 3.5% to 26% with the higher rates in lung and heart recipients<a class="elsevierStyleCrossRef" href="#bib0375"><span class="elsevierStyleSup">15</span></a> followed by liver and kidney transplant. The risk also depends on the degree of immunosuppression, metabolic and technical postoperative factors, and infection with immunomodulatory viruses such as cytomegalovirus (CMV).<a class="elsevierStyleCrossRef" href="#bib0380"><span class="elsevierStyleSup">16</span></a> In this population, IA is associated with high rates of graft loss and mortality, from 36% in heart recipients to 88% in liver recipients.<a class="elsevierStyleCrossRef" href="#bib0375"><span class="elsevierStyleSup">15</span></a></p><p id="par0060" class="elsevierStylePara elsevierViewall">In high-risk immunocompromised patients, antifungal prophylaxis becomes an effective preventive strategy. However, breakthrough invasive fungal infections (bIFI) may occur,<a class="elsevierStyleCrossRef" href="#bib0385"><span class="elsevierStyleSup">17</span></a> usually associated to different risk factors: pathogen-related, antifungal drug-drug interactions, iatrogenic or environmental or the use of immunomodulators. bIFI are defined as those infections arising during exposure to an antifungal drug, regardless of its indication (prophylactic, empiric, pre-emptive or targeted). bIFI may occur early or late during antifungal exposure,<a class="elsevierStyleCrossRef" href="#bib0390"><span class="elsevierStyleSup">18</span></a> and the emergence of cryptic species and non-fumigatus <span class="elsevierStyleItalic">Aspergillus</span> species with their possible antifungal resistance becomes a significant concern. Rates of bIFI in haematological patients are ranged from 3.1% to 13% of the cases.</p><p id="par0065" class="elsevierStylePara elsevierViewall">New risk factors for IA have been identified along the years. These include severe liver disease,<a class="elsevierStyleCrossRef" href="#bib0395"><span class="elsevierStyleSup">19</span></a> malnutrition, advanced HIV infection (CD4 cell count less than 100<span class="elsevierStyleHsp" style=""></span>cells/μL), advanced diabetes mellitus, chronic obstructive pulmonary disease (COPD),<a class="elsevierStyleCrossRef" href="#bib0400"><span class="elsevierStyleSup">20</span></a> solid tumours, and critically ill condition requiring ICU admission. The isolation of <span class="elsevierStyleItalic">A. fumigatus</span> from respiratory secretions is a common occurrence in COPD patients, but little is known about its significance and implications. In a recent systematic review, it was estimated that up to 3.9% of COPD patients admitted to hospital may have IA.<a class="elsevierStyleCrossRef" href="#bib0405"><span class="elsevierStyleSup">21</span></a> Moreover, <span class="elsevierStyleItalic">Aspergillus</span>-colonised patients with GOLD stage 3 or 4 were more likely to have IA than those with earlier stages of COPD.</p><p id="par0070" class="elsevierStylePara elsevierViewall">In the group of critically ill patients, systemic corticosteroid treatment and pre-existing respiratory or cardiovascular conditions are particularly relevant. <span class="elsevierStyleItalic">Aspergillus</span> spp. are isolated from lower respiratory tract samples in 0.7–7% of critically ill patients, but the diagnosis of IA can be challenging given the lack of consensus on how to define IA in this population.<a class="elsevierStyleCrossRef" href="#bib0410"><span class="elsevierStyleSup">22</span></a> Some algorithms have been proposed, which have guided clinicians to identify critically ill patient with suspected aspergillosis.<a class="elsevierStyleCrossRef" href="#bib0415"><span class="elsevierStyleSup">23</span></a></p><p id="par0075" class="elsevierStylePara elsevierViewall">Severe respiratory viral infections have been described as an important risk factor for fungal infections. From a pathophysiological point of view, disruption in the epithelial barrier, the suppression of cellular immunity, the alteration of phagocytic activity, the dysfunction of mucociliary clearance, and the release of cytokines are just some potential explanations for the coexistence of viral and fungal infections.<a class="elsevierStyleCrossRef" href="#bib0420"><span class="elsevierStyleSup">24</span></a></p><p id="par0080" class="elsevierStylePara elsevierViewall">Among patients with influenza who were admitted to the ICU and developed acute respiratory distress syndrome (ARDS), the incidence rates of influenza virus-associated pulmonary aspergillosis (IAPA) of up to 19% have been described, with higher mortality compared to influenza patients without IAPA (51% vs 28% respectively).<a class="elsevierStyleCrossRef" href="#bib0425"><span class="elsevierStyleSup">25</span></a></p><p id="par0085" class="elsevierStylePara elsevierViewall">In recent years, COVID-19 associated pulmonary aspergillosis (CAPA) have also been described. A European Confederation of Medical Mycology (ECMM) multinational study with 592 patients, found that prevalence varied widely between centres with a median prevalence of 11% (1.7–26.8%). CAPA is usually diagnosed at a median of 8 days after ICU admission and more frequently in elderly patients who needed mechanical ventilation and received tocilizumab. CAPA was associated with a nearly two-fold increased risk of ICU mortality compared with patients who did not develop CAPA (71% versus 43%).<a class="elsevierStyleCrossRef" href="#bib0430"><span class="elsevierStyleSup">26</span></a></p><p id="par0090" class="elsevierStylePara elsevierViewall">Establishing an adequate differentiation between colonisation and infection in patients with respiratory isolation of <span class="elsevierStyleItalic">Aspergillus</span> spp and viral co-infections, the absence of classical associated IA host factors in these patients with non-specific radiological findings, makes the IAPA and CAPA definition an additional challenge. This may explain the variability in the incidence rates reported in the literature due to not meeting the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSGERC) criteria. For this reason, different experts have led to the appearance of new specific criteria that have homogenised the classification of these two super-infections.<a class="elsevierStyleCrossRefs" href="#bib0435"><span class="elsevierStyleSup">27,28</span></a></p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Clinical presentation</span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Invasive pulmonary aspergillosis</span><p id="par0095" class="elsevierStylePara elsevierViewall">Invasive pulmonary aspergillosis (IPA) is an acute progressive infection that occurs in severely immunocompromised patients and has a high associated mortality. It is typically presenting as lung nodule/s, with or without “halo sign”, observed in chest CT-scan.</p><p id="par0100" class="elsevierStylePara elsevierViewall">Clinical manifestations of IPA include cough, fever, chest or pleuritic pain, dyspnoea and haemoptysis.<a class="elsevierStyleCrossRef" href="#bib0305"><span class="elsevierStyleSup">1</span></a> Depending on the route of dissemination, aspergillosis can be broncho-invasive or angio-invasive. Angio-invasive forms are more frequently seen in neutropenic patients and are characterised by invasion of small and medium-sized pulmonary arteries leading to thrombosis, ischaemia, necrosis and finally dissemination. Non-neutropenic patients (solid organ transplant, AIDS, chronic granulomatous disease, critically-ill ICU patients, chronic corticosteroid therapy) usually do not have evidence of angioinvasion.</p><p id="par0105" class="elsevierStylePara elsevierViewall">Broncho-invasive forms are more frequent in patients with respiratory tract disruption such as COPD, asthma and orotracheal intubation. The broncho-invasive form has less frequent dissemination than angio-invasive forms, but it has also been observed in heart transplant recipients associating high mortality. Although, this could be related to delayed antifungal treatment due to its difficulties in the diagnosis.<a class="elsevierStyleCrossRef" href="#bib0445"><span class="elsevierStyleSup">29</span></a></p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Tracheobronchial aspergillosis</span><p id="par0110" class="elsevierStylePara elsevierViewall">Tracheobronchial aspergillosis refers to the invasion of <span class="elsevierStyleItalic">Aspergillus</span> into the trachea and bronchi. Three forms are described: pseudomembranous, ulcerative and obstructive.</p><p id="par0115" class="elsevierStylePara elsevierViewall">Fungal tracheobronchitis is usually observed in immunosuppressed patients, lung transplant recipients and those with compromised airways.<a class="elsevierStyleCrossRef" href="#bib0450"><span class="elsevierStyleSup">30</span></a> Recently it has also been observed in IAPA and CAPA patients. Diagnosis can be challenging, as symptoms may be unspecific (cough, stridor, haemoptysis) and bronchoscopy becomes a key tool.</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Extrapulmonary aspergillosis</span><p id="par0120" class="elsevierStylePara elsevierViewall">Extrapulmonary aspergillosis can involve organs such as heart, bone or soft tissues, paranasal sinuses, prostate or kidney. Rhinosinusal aspergillosis is the most common, characterised by pain, facial swelling, purulent rhinorrhoea, and nasal obstruction. Subacute forms may be seen in patients with lower degrees of immunosuppression, but rhino-orbital extension is usually observed in patients with prolonged neutropenia.<a class="elsevierStyleCrossRef" href="#bib0455"><span class="elsevierStyleSup">31</span></a> The symptoms of extrapulmonary aspergillosis will differ depending on the affected organ and host immune system. The diagnosis often requires a combination of imaging studies such as computed tomography (CT) scan or magnetic resonance imaging (MRI), biopsy, and laboratory tests. Extrapulmonary aspergillosis usually demands a multidisciplinary approach and often requires surgical debridement.</p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Central nervous system involvement</span><p id="par0125" class="elsevierStylePara elsevierViewall">CNS involvement represents one of the most severe forms of IA, generally affecting patients with haematological malignancies, autoimmune diseases requiring corticosteroid treatment or SOT recipients. Usually, patients have a history of prior or concurrent IPA or invasive rhinosinusitis aspergillosis, although primary CNS forms have also been described. Brain infiltration can lead to devastating neurological complications. Most of the times, cerebrospinal fluid analysis is not helpful for diagnosis since CNS aspergillosis does not usually present as meningitis.<a class="elsevierStyleCrossRef" href="#bib0305"><span class="elsevierStyleSup">1</span></a> Treatment is challenging due to the limited penetration of antifungal drugs into the CNS. Available data show improved survival rates in patients undergoing neurosurgery (28.6% mortality compared to 60.4% among patients who received only antifungals).<a class="elsevierStyleCrossRef" href="#bib0460"><span class="elsevierStyleSup">32</span></a></p></span></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Diagnosis</span><p id="par0130" class="elsevierStylePara elsevierViewall">The diagnosis of IA is a challenge for clinicians and it usually combines three essential factors: host, clinical/radiological, and microbiological criteria.</p><p id="par0135" class="elsevierStylePara elsevierViewall">The revised EORTC/MSGERC criteria (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>) focus primarily in patients with underlying haematological malignancies and a classical presentation of IA.<a class="elsevierStyleCrossRef" href="#bib0465"><span class="elsevierStyleSup">33</span></a></p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0140" class="elsevierStylePara elsevierViewall">“Probable” IA requires the presence of a host factor, a clinical finding and mycological evidence. Cases that meet the criteria for a host factor with clinical presentation but without mycological evidence, are considered “Possible”.</p><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Histology</span><p id="par0145" class="elsevierStylePara elsevierViewall">Unequivocal diagnosis of IA requires tissue biopsy demonstrating invasion by hyphae on microscopic examination and/or recovery of the mould from sterile fluids. This criterion will determine the diagnosis of “Proven” IA according to any diagnostic criteria. Staining techniques such as Gomori-Grocott (silver methenamine) or the Schiff technique (PAS) are the most commonly used. It is important to remember that <span class="elsevierStyleItalic">Aspergillus</span> appearance in a biopsy is similar to other septate moulds such as <span class="elsevierStyleItalic">Fusarium</span>, so culture or PCR is needed for species identification.</p><p id="par0150" class="elsevierStylePara elsevierViewall">Obtaining tissue for analysis may be challenging due to underlying host factors, such as thrombocytopenia or haemodynamic instability, precluding invasive diagnostic testing.</p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Radiological findings</span><p id="par0155" class="elsevierStylePara elsevierViewall">Classical radiological CT-scan findings of angio-invasive aspergillosis usually include macronodule(s)<span class="elsevierStyleHsp" style=""></span>><span class="elsevierStyleHsp" style=""></span>1<span class="elsevierStyleHsp" style=""></span>cm, which may be surrounded by a halo of ground-glass attenuation (“halo sign”, usually in early phases in neutropenic patients). This sign refers to a central nodule surrounded by a halo of ground-glass attenuation caused by local damage and inflammatory response triggered by <span class="elsevierStyleItalic">Aspergillus</span> invasion. Other presentations consist of pleural based wedge-shaped areas of consolidation, alveolar consolidations, masses (especially in SOT recipients), internal low attenuation, reverse halo sign (most commonly observed in mucormycosis), cavity or “air-crescent” sign (delayed finding, usually in temporary association with neutrophil recovery or even in response to antifungal treatment), ground glass opacities and pleural effusion. Broncho-invasive forms may appear as tracheal or bronchial wall thickening, centrilobular nodules with tree in bud appearance in a patchy distribution, predominant peribronchial areas of consolidation or broncho-pneumonia.<a class="elsevierStyleCrossRef" href="#bib0470"><span class="elsevierStyleSup">34</span></a></p></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Culture-based methods</span><p id="par0160" class="elsevierStylePara elsevierViewall">The appropriate sample for culture depends on the site of infection. Respiratory samples are needed in cases of IPA, which is the most frequent clinical presentation. The isolation of <span class="elsevierStyleItalic">Aspergillus</span> from any respiratory sample can represent colonisation; for this reason, it is crucial to obtain the best quality sample as possible and identify other associated factors (host and radiological findings). Bronchoscopy examination is recommended, primarily for two reasons. Firstly, it allows the observation of the affected region, providing a visual assessment and enabling targeted sampling. Secondly, the bronchoalveolar lavage fluid (BALf) is a validated sample widely accepted in most guidelines for conducting mycological testing. Sputum, broncho-aspirate or tracheal aspirate may also be used.</p><p id="par0165" class="elsevierStylePara elsevierViewall">Diagnosis could also be addressed with positive cultures from a normally sterile site, such as cerebrospinal fluid (CSF) or blood stream, although these are rarely positive. <span class="elsevierStyleItalic">A. fumigatus</span> colonies grow at 37<span class="elsevierStyleHsp" style=""></span>°C, appearing flat, compact, with a velvety texture, and a whitish colour that changes to bluish-green or greyish-green. Culture results will also allow antifungal susceptibility testing of the <span class="elsevierStyleItalic">Aspergillus</span> species identified.</p><p id="par0170" class="elsevierStylePara elsevierViewall">Direct examination, such as calcofluor white stain, become useful in cases of high suspicion, giving results in about 30 minutes and allowing prompt antifungal treatment. Despite its lower sensitivity ranging from 30 to 40%, a positive result may imply a high fungal burden and, therefore, poor prognosis.<a class="elsevierStyleCrossRef" href="#bib0475"><span class="elsevierStyleSup">35</span></a></p><p id="par0175" class="elsevierStylePara elsevierViewall">Identification techniques based on MALDI-TOF or PCR improve the diagnosis of IA; however, the availability of an adequate sample is still one of the significant constraints for a correct diagnosis. For this reason, different non-culture-based methods have been developed over the last decades, providing the clinician with an exhaustive diagnostic resource.</p></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Non-culture-based methods</span><p id="par0180" class="elsevierStylePara elsevierViewall">Alternative diagnostic methods have been developed considering the problems associated with acquiring adequate samples and the widely different meanings of cultures results.<a class="elsevierStyleCrossRef" href="#bib0480"><span class="elsevierStyleSup">36</span></a> Combining non-culture-based techniques and conventional methods, as well as the different non-culture-based techniques, is recommended in order to improve the diagnosis sensitivity.<a class="elsevierStyleCrossRef" href="#bib0485"><span class="elsevierStyleSup">37</span></a></p><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090"><span class="elsevierStyleItalic">Aspergillus</span> antigen (or Galactomannan)</span><p id="par0185" class="elsevierStylePara elsevierViewall">Galactomannan (GM) is a polysaccharide found in the cell walls of some fungi, including <span class="elsevierStyleItalic">Aspergillus</span>. In the context of IA, detecting galactomannan in biological fluids such as serum, cerebrospinal fluid, and BALf is used as a diagnostic method and reveals the presence of the galactomannan antigen released by <span class="elsevierStyleItalic">Aspergillus</span> hyphae during growth.</p><p id="par0190" class="elsevierStylePara elsevierViewall">Currently there are two platforms for galactomannan detection: the Platelia GM ELISA (Bio-Rad)®, which was the first FDA approved assay for testing IA with greater validation and experience of use, and the <span class="elsevierStyleItalic">Aspergillus</span> galactomannan Ag Virclia Monotest (Vircell S.L)®, which uses chemiluminescence detection. Typically assessed through commercial immunoassays, point-of-care (POC) lateral flow device (LFD) and the lateral flow assay (LFA) are arising as useful for the diagnosis of IA in patients with haematologic malignancy, although further assessment in the non-neutropenic setting is needed.<a class="elsevierStyleCrossRef" href="#bib0490"><span class="elsevierStyleSup">38</span></a></p><p id="par0195" class="elsevierStylePara elsevierViewall">GM is reported as optical density (OD) index. An OD index<span class="elsevierStyleHsp" style=""></span>≥<span class="elsevierStyleHsp" style=""></span>0.5 is generally considered to be a positive result in serum and >1.0 in BAL (Platelia GM test). Sensitivity and specificity of serum cut-off<span class="elsevierStyleHsp" style=""></span>≥<span class="elsevierStyleHsp" style=""></span>0.5 is 56–89% and 67–99% respectively, depending on the degree of immunosuppression and neutropenia, being more useful in neutropenic population. Cut-off of 0.5 has proven high sensitivity in haematological patients in the absence of mould-active prophylaxis. <span class="elsevierStyleItalic">Aspergillus</span> galactomannan Ag Virclia Monotest (Vircell S.L)® had a cut-off point in serum and BAL of 0.2.</p><p id="par0200" class="elsevierStylePara elsevierViewall">The low pretest risk of IA in the context of effective prophylaxis (12%), makes serum GM surveillance of asymptomatic patients unreliable, as all results would be either negative or false positive. For this reason, serial screening is not recommended in patients under prophylaxis.<a class="elsevierStyleCrossRef" href="#bib0470"><span class="elsevierStyleSup">34</span></a></p><p id="par0205" class="elsevierStylePara elsevierViewall">Serum GM has also been proposed as a monitoring therapeutic response tool in patients with haematological malignancies and may apply to other populations at risk.<a class="elsevierStyleCrossRef" href="#bib0495"><span class="elsevierStyleSup">39</span></a> However, several factors could lead to false positive results, including using certain albumin products, previous use of echinocandins, plasma lite infusion, transfusions, or cross-reactivity with non-<span class="elsevierStyleItalic">Aspergillus</span> fungal species.</p><p id="par0210" class="elsevierStylePara elsevierViewall">In BALf samples, the cut-off with higher sensitivity and specificity is ≥1 (88% and 81% respectively). This determination is especially relevant in broncho-invasive forms or critically ill patients.</p><p id="par0215" class="elsevierStylePara elsevierViewall">GM positivity (>0.5) in CSF could be useful, but is not standardised nor validated.<a class="elsevierStyleCrossRef" href="#bib0500"><span class="elsevierStyleSup">40</span></a> In the EORTC/MSGERC consensus definition, a cut-off of ≥1.0 in CSF is considered a microbiological criterion for cerebral aspergillosis.</p></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">1,3 β-<span class="elsevierStyleSmallCaps">d</span>-glucan</span><p id="par0220" class="elsevierStylePara elsevierViewall">1,3-β-<span class="elsevierStyleSmallCaps">d</span>-Glucan (BDG) is a panfungal biomarker, representing a polysaccharide component of most fungal cell walls which is released into the bloodstream during diverse invasive fungal infections: <span class="elsevierStyleItalic">Aspergillus</span>, <span class="elsevierStyleItalic">Candida</span>, <span class="elsevierStyleItalic">Fusarium</span>, <span class="elsevierStyleItalic">Trichosporon</span>, <span class="elsevierStyleItalic">Saccharomyces</span>, <span class="elsevierStyleItalic">Acremonium</span>, and <span class="elsevierStyleItalic">Pneumocystis jirovecii.</span></p><p id="par0225" class="elsevierStylePara elsevierViewall">There are different commercial assays with different cut-offs available for its determination. Some of the most used are:<ul class="elsevierStyleList" id="lis0005"><li class="elsevierStyleListItem" id="lsti0005"><span class="elsevierStyleLabel">-</span><p id="par0230" class="elsevierStylePara elsevierViewall">FUJIFILM Wako (Osaka, Japan). Cut-off of ≥11<span class="elsevierStyleHsp" style=""></span>pg/mL was recommended by the manufacturers, but has been related to low sensitivity. Proposed cut-off of ≥7<span class="elsevierStyleHsp" style=""></span>pg/mL increased the sensitivity up to 80% without decreasing specificity<a class="elsevierStyleCrossRef" href="#bib0505"><span class="elsevierStyleSup">41</span></a> and has excellent correlation with GM.</p></li><li class="elsevierStyleListItem" id="lsti0010"><span class="elsevierStyleLabel">-</span><p id="par0235" class="elsevierStylePara elsevierViewall">Fungitell Assay (Cape Cod, INC). Cut-off of ≥80<span class="elsevierStyleHsp" style=""></span>pg/mL associates a sensitivity and specificity of 78–80% and 63–81%, respectively.</p></li></ul></p><p id="par0240" class="elsevierStylePara elsevierViewall">Although not included as a microbiological criterion in the latest EORTC/MSGERC updated consensus for the diagnosis of mould infections, it is proposed as a useful tool for this purpose.</p></span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Molecular diagnosis</span><p id="par0245" class="elsevierStylePara elsevierViewall">Polymerase chain reaction (PCR) has been used for several years now. In fact, PCR has been included in the latest EORTC/MSGERC update for diagnosing mould infections as one of the microbiological criteria. Nevertheless, there is ongoing debate about its sensitivity and specificity due to the different available procedures and techniques, with some commercial kits appearing recently.<a class="elsevierStyleCrossRef" href="#bib0510"><span class="elsevierStyleSup">42</span></a></p><p id="par0250" class="elsevierStylePara elsevierViewall">PCR can be performed in serum, plasma, whole blood, and BALf. Data have been evaluated most extensively in adults with haematologic malignancies and HSCT and more recently in ICU patients.<a class="elsevierStyleCrossRef" href="#bib0515"><span class="elsevierStyleSup">43</span></a> Mikulska et al. reported <span class="elsevierStyleItalic">Aspergillus</span>-PCR in BALf sensitivity of 40% in ICU COVID-19 patients, 67% in non-COVID-19 ICU patients and 92% in the immunocompromised using the AsperGenius commercial kit. Another recent study has reported an improved accuracy of <span class="elsevierStyleItalic">Aspergillus</span> PCR targeting cell-free DNA (DNAemia) in plasma samples, with a sensitivity of PCR of 86.0% for proven/probable IA.<a class="elsevierStyleCrossRef" href="#bib0520"><span class="elsevierStyleSup">44</span></a></p><p id="par0255" class="elsevierStylePara elsevierViewall">In addition, PCR is being studied as a new molecular approach to detect resistance, as for example cyp51A protein mutation detection. The development of these new applications can help overwhelmed some of the culture methods limitations. However, the impact of isolated PCR resistance detection in the absence of other positive diagnostic methods (GM or cultured-based) remains to be analysed, as mortality was not affected in those who had PCR positive results compared to negative in a recent prospective multicentric study which evaluate the clinical value of the AsperGenius PCR assay in haematology patients.<a class="elsevierStyleCrossRef" href="#bib0525"><span class="elsevierStyleSup">45</span></a></p></span></span></span><span id="sec0085" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Treatment</span><p id="par0260" class="elsevierStylePara elsevierViewall">The approach to the IA treatment requires consideration of both the severity of the infection and the host factors. Any patient with clinical suspicion of IA, should receive antifungal therapy after diagnostic samples have been obtained, if possible, whether or not the EORTC/MSGERC criteria are met, as these have been established to homogenise definitions for clinical trials and not for clinical decisions.<a class="elsevierStyleCrossRef" href="#bib0470"><span class="elsevierStyleSup">34</span></a></p><p id="par0265" class="elsevierStylePara elsevierViewall">Key antifungal agents like voriconazole, isavuconazole, liposomal amphotericin B, and posaconazole are main options for IA management. Their dosages are described in <a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>.</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><span id="sec0090" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Triazoles</span><p id="par0270" class="elsevierStylePara elsevierViewall">The triazoles apply their antifungal effects by inhibiting the cytochrome P450 (CYP), blocking the transformation of lanosterol to ergosterol, a compound found in the fungi cell membranes, inhibiting fungal cell growth and replication.</p><p id="par0275" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Voriconazole</span> is a second-generation triazole available in oral and IV formulations. It remains the treatment of choice for most clinical IA forms, both pulmonary and extrapulmonary.<a class="elsevierStyleCrossRefs" href="#bib0470"><span class="elsevierStyleSup">34,46</span></a></p><p id="par0280" class="elsevierStylePara elsevierViewall">It is important to remark that voriconazole needs therapeutic drug monitoring (TDM), given its unpredictable, nonlinear pharmacokinetics with extensive interpatient and intrapatient variation in serum levels. TDM is strongly recommended for voriconazole, but in general for all azoles. Routine TDM of voriconazole may reduce drug discontinuation due to adverse events and improve the treatment response.<a class="elsevierStyleCrossRef" href="#bib0535"><span class="elsevierStyleSup">47</span></a> A plasma trough concentration of 1–5.5<span class="elsevierStyleHsp" style=""></span>mg/L is considered suitable for most patients receiving voriconazole, prophylaxis or treatment. Plasma levels should be monitored between 2 and 5 days after initiation of therapy, and repeated the following week to confirm that the patient has achieved the steady-state.<a class="elsevierStyleCrossRef" href="#bib0470"><span class="elsevierStyleSup">34</span></a> The most frequent adverse reactions are gastrointestinal, visual, hepatotoxicity, skin reactions and nephrotoxicity.</p><p id="par0285" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Isavuconazole</span> is a second-generation broad-spectrum triazole available in oral and IV formulations, with activity against yeasts, dimorphic fungi, and moulds.<a class="elsevierStyleCrossRef" href="#bib0540"><span class="elsevierStyleSup">48</span></a> Isavuconazole presents significant advantages which make it an attractive alternative for the management of aspergillosis, including its broad-spectrum activity, absence of QTc interval prolongation, more predictable pharmacokinetics, drug-drug interaction profile, and good tolerability.<a class="elsevierStyleCrossRef" href="#bib0545"><span class="elsevierStyleSup">49</span></a> In a phase-3 clinical trial, isavuconazole demonstrated comparable efficacy to voriconazole for the primary treatment of suspected invasive mould infections, with fewer study-drug-related adverse events.<a class="elsevierStyleCrossRef" href="#bib0550"><span class="elsevierStyleSup">50</span></a> No TDM monitoring is required, although it is recommended in some selected patients, such as those with high body mass index (BMI) and SOFA score in ICU, suspicion of drug interaction, infectious by moulds with elevated MICs or patients who are unresponsive to treatment.<a class="elsevierStyleCrossRefs" href="#bib0470"><span class="elsevierStyleSup">34,51</span></a></p><p id="par0290" class="elsevierStylePara elsevierViewall">Voriconazole and Isavuconazole should be considered drugs of choice for primary treatment of IA in patients not receiving triazole prophylaxis.<a class="elsevierStyleCrossRef" href="#bib0560"><span class="elsevierStyleSup">52</span></a></p><p id="par0295" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Posaconazole</span>, available in oral and IV formulations, also has a broad-spectrum activity against both mould and yeasts. Although more widely used as primary antifungal prophylaxis in high risk onco-haematological patients,<a class="elsevierStyleCrossRef" href="#bib0565"><span class="elsevierStyleSup">53</span></a> its usefulness as a salvage therapy has been widely described.<a class="elsevierStyleCrossRef" href="#bib0570"><span class="elsevierStyleSup">54</span></a> A recent study also demonstrated non-inferiority of posaconazole compared to voriconazole as first-line treatment of IPA.<a class="elsevierStyleCrossRef" href="#bib0575"><span class="elsevierStyleSup">55</span></a> TDM is recommended to achieve plasma levels above 0.7<span class="elsevierStyleHsp" style=""></span>mg/L for prophylaxis, and >1<span class="elsevierStyleHsp" style=""></span>mg/L if the patient is receiving posaconazole as treatment.<a class="elsevierStyleCrossRef" href="#bib0470"><span class="elsevierStyleSup">34</span></a></p></span><span id="sec0095" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">Liposomal amphotericin B</span><p id="par0300" class="elsevierStylePara elsevierViewall">Amphotericin B, a polyene-class antifungal, is currently only available in IV formulations, though oral formulations are under investigation. His mechanism is based on binding to ergosterol, leading to the formation of pores in the fungal membrane, resulting in fungal cell death. Liposomal amphotericin B (L-AmB) use lipid-based vesicles for improved pharmacokinetics and reduced toxicity. L-AmB demonstrates a broad antifungal spectrum, enhancing efficacy against diverse pathogens. Despite improved safety, infusion-related reactions and adverse effects like electrolyte abnormalities, anaemia, and renal dysfunction may still occur.</p><p id="par0305" class="elsevierStylePara elsevierViewall">L-AmB is an alternative for primary or salvage therapy for patients who are intolerant, had hepatitis or are refractory to voriconazole or isavuconazole. Also for patients with suspected or confirmed triazole resistance, or when triazole use is not desirable due to drug interactions.<a class="elsevierStyleCrossRef" href="#bib0560"><span class="elsevierStyleSup">52</span></a></p></span><span id="sec0100" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">Echinocandins</span><p id="par0310" class="elsevierStylePara elsevierViewall">The echinocandins (caspofungin, anidulafungin, micafungin, rezafungin) have a fungistatic activity against <span class="elsevierStyleItalic">Aspergillus</span> spp. inhibiting BDG synthase, a necessary enzyme for the synthesis of the cell wall of several fungi. Echinocandins are rarely used as monotherapy due to limited clinical efficacy, and therefore strongly recommended only in combination with other antifungals.</p></span><span id="sec0105" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0125">New antifungal options</span><p id="par0315" class="elsevierStylePara elsevierViewall">New antifungal therapeutic options and new formulations of known antifungals have been developed in recent years; however, some are still in the early stages of study. We will focus in this review on describing briefly some of the characteristics of those currently active against <span class="elsevierStyleItalic">Aspergillus.</span><a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a> resumes main characteristics of each agent.<a class="elsevierStyleCrossRef" href="#bib0580"><span class="elsevierStyleSup">56</span></a></p><elsevierMultimedia ident="tbl0015"></elsevierMultimedia></span><span id="sec0110" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0130">Duration of the therapy</span><p id="par0320" class="elsevierStylePara elsevierViewall">The duration of treatment of IA is a topic of ongoing debate. Historically, a duration of a minimum of 6–12 weeks has been recommended<a class="elsevierStyleCrossRef" href="#bib0530"><span class="elsevierStyleSup">46</span></a>; although, recently management guidelines have suggested that treatment duration could be adapted individually depending on the site and extent of infection, clinical or radiological response, immune reconstitution and recovery from GvHD in HSCT.<a class="elsevierStyleCrossRef" href="#bib0470"><span class="elsevierStyleSup">34</span></a></p><p id="par0325" class="elsevierStylePara elsevierViewall">Regular monitoring through clinical assessments, imaging studies, and laboratory tests is crucial to estimate treatment efficacy and guide decisions regarding the duration of antifungal therapy. Serum GM and its kinetics seem to correlate with response and survival in patients with IA<a class="elsevierStyleCrossRef" href="#bib0585"><span class="elsevierStyleSup">57</span></a> and, therefore, presents as an effective tool to provide better accuracy in the duration of IA therapy.</p><p id="par0330" class="elsevierStylePara elsevierViewall">Radiological follow-up (preferably with a CT-scan) is recommended after at least two weeks of therapy. In addition, recent studies are raising the cost-effectiveness of PET/CT in differentiating active lesions from residual lesions on CT in patients showing a favourable clinical course. In haematological patients, a flow-chart algorithm has been proposed to assess antifungal therapy duration based on these results.<a class="elsevierStyleCrossRef" href="#bib0590"><span class="elsevierStyleSup">58</span></a></p></span><span id="sec0115" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0135">Combination therapy</span><p id="par0335" class="elsevierStylePara elsevierViewall">The combination of antifungal agents is not primarily recommended as first-line agent in IA treatment. As salvage therapy, however, the use of L-AmB or triazole (if not used as first line) associating echinocandins can be useful. No study has shown that combination therapy is beneficial for culture-documented IA. In clinical trials, a subgroup analysis revealed that early treatment with voriconazole and anidulafungin in haematological patients diagnosed with invasive aspergillosis (IA) based on positive biomarkers (GM) and CT findings led to an 11.5% reduction in 60-day mortality, suggesting potential benefits in this specific patient population.<a class="elsevierStyleCrossRefs" href="#bib0595"><span class="elsevierStyleSup">59,60</span></a></p><p id="par0340" class="elsevierStylePara elsevierViewall">Future studies are needed to clarify whether there is indeed superiority of combination therapy over monotherapy. A clinical trial is ongoing to asses if triazoles in combination with echinocandin compared to azole monotherapy, is superior treating probable/proven IA by EORTC/MSGERC definition (NLM, <a href="ctgov:NCT04876716">NCT04876716</a>).</p><p id="par0345" class="elsevierStylePara elsevierViewall">Combination therapy could be usefulness in specific settings such as: (a) severely immunocompromised patients with disseminated breakthrough fungal infections caused by resistant <span class="elsevierStyleItalic">Aspergillus</span> spp. or mixed mould infections; (b) high azole resistance rates areas (>10%), especially in severely ill patients<a class="elsevierStyleCrossRef" href="#bib0560"><span class="elsevierStyleSup">52</span></a>; (c) lacking response to monotherapy.</p><p id="par0350" class="elsevierStylePara elsevierViewall">For CNS infections, given the poor brain fluid penetration of echinocandins, combination therapy may be complicated due to concerns about antagonism between voriconazole and LAmB. However, this antagonism has only been demonstrated in vitro.</p><p id="par0355" class="elsevierStylePara elsevierViewall">A flowchart about diagnosis and therapy in IA has been created (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>), following the main recommendations developed in the clinical practice guidelines for the management of invasive Aspergillus diseases: GEMICOMED-SEIMC/REIPI Update 2018.<a class="elsevierStyleCrossRef" href="#bib0560"><span class="elsevierStyleSup">52</span></a></p><elsevierMultimedia ident="fig0010"></elsevierMultimedia></span></span><span id="sec0120" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0140">Conclusions</span><p id="par0360" class="elsevierStylePara elsevierViewall">Invasive aspergillosis has historically been associated with a well-known clinical presentation in a population characterised by intense immunosuppression. In recent years, IA has increasingly been found outside this classic context, affecting new at-risk populations. This has made it necessary to increase suspicion, update the definition criteria and incorporate new diagnostic methods.</p><p id="par0365" class="elsevierStylePara elsevierViewall">Treatment still relies on triazoles and liposomal amphotericin B, with new antifungals that have a promising role in some growing concerns such as azole resistance. Developing new strategies to manage this infection becomes a life-saving approach for IA.</p></span><span id="sec0125" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0145">Ethical considerations</span><p id="par0370" class="elsevierStylePara elsevierViewall">No patient data appears in this manuscript, so written informed consent was not obtained.</p></span><span id="sec0130" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0150">Funding</span><p id="par0375" class="elsevierStylePara elsevierViewall">This research received no funding.</p></span><span id="sec0135" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0155">Conflict of interests</span><p id="par0380" class="elsevierStylePara elsevierViewall">M.M. has received speaker fees from Gilead Sciences, MSD and Pfizer, outside the submitted work.</p><p id="par0385" class="elsevierStylePara elsevierViewall">P.M. has received speaker fees from Pfizer, MSD and Gilead Sciences, outside the submitted work.</p><p id="par0390" class="elsevierStylePara elsevierViewall">J.F. has received financial compensation for advising/consultancy and has received grant support from Astellas Pharma, Gilead Sciences, MSD, and Pfizer, outside the submitted work.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:15 [ 0 => array:3 [ "identificador" => "xres2225928" "titulo" => "Abstract" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0005" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec1864107" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres2225927" "titulo" => "Resumen" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0010" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec1864108" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:2 [ "identificador" => "sec0010" "titulo" => "Aetiology" ] 6 => array:2 [ "identificador" => "sec0015" "titulo" => "Pathogenesis and risk factors" ] 7 => array:3 [ "identificador" => "sec0020" "titulo" => "Clinical presentation" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "sec0025" "titulo" => "Invasive pulmonary aspergillosis" ] 1 => array:2 [ "identificador" => "sec0030" "titulo" => "Tracheobronchial aspergillosis" ] 2 => array:2 [ "identificador" => "sec0035" "titulo" => "Extrapulmonary aspergillosis" ] 3 => array:2 [ "identificador" => "sec0040" "titulo" => "Central nervous system involvement" ] ] ] 8 => array:3 [ "identificador" => "sec0045" "titulo" => "Diagnosis" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "sec0050" "titulo" => "Histology" ] 1 => array:2 [ "identificador" => "sec0055" "titulo" => "Radiological findings" ] 2 => array:2 [ "identificador" => "sec0060" "titulo" => "Culture-based methods" ] 3 => array:3 [ "identificador" => "sec0065" "titulo" => "Non-culture-based methods" "secciones" => array:3 [ 0 => array:2 [ "identificador" => "sec0070" "titulo" => "Aspergillus antigen (or Galactomannan)" ] 1 => array:2 [ "identificador" => "sec0075" "titulo" => "1,3 β-d-glucan" ] 2 => array:2 [ "identificador" => "sec0080" "titulo" => "Molecular diagnosis" ] ] ] ] ] 9 => array:3 [ "identificador" => "sec0085" "titulo" => "Treatment" "secciones" => array:6 [ 0 => array:2 [ "identificador" => "sec0090" "titulo" => "Triazoles" ] 1 => array:2 [ "identificador" => "sec0095" "titulo" => "Liposomal amphotericin B" ] 2 => array:2 [ "identificador" => "sec0100" "titulo" => "Echinocandins" ] 3 => array:2 [ "identificador" => "sec0105" "titulo" => "New antifungal options" ] 4 => array:2 [ "identificador" => "sec0110" "titulo" => "Duration of the therapy" ] 5 => array:2 [ "identificador" => "sec0115" "titulo" => "Combination therapy" ] ] ] 10 => array:2 [ "identificador" => "sec0120" "titulo" => "Conclusions" ] 11 => array:2 [ "identificador" => "sec0125" "titulo" => "Ethical considerations" ] 12 => array:2 [ "identificador" => "sec0130" "titulo" => "Funding" ] 13 => array:2 [ "identificador" => "sec0135" "titulo" => "Conflict of interests" ] 14 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2023-11-30" "fechaAceptado" => "2024-01-30" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec1864107" "palabras" => array:4 [ 0 => "Invasive aspergillosis" 1 => "<span class="elsevierStyleItalic">Aspergillus fumigatus</span>" 2 => "Pulmonary aspergillosis" 3 => "Invasive fungal infections" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec1864108" "palabras" => array:4 [ 0 => "Aspergilosis invasiva" 1 => "<span class="elsevierStyleItalic">Aspergillus fumigatus</span>" 2 => "Aspergilosis pulmonar" 3 => "Infección fúngica invasiva" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Invasive aspergillosis (IA) is a severe fungal infection caused by <span class="elsevierStyleItalic">Aspergillus</span> species, particularly <span class="elsevierStyleItalic">Aspergillus fumigatus</span>, although new species, sometimes resistant to antifungals are becoming more common. IA predominantly affects immunocompromised patients, such as those with haematological malignancies, solid organ transplant recipients, and critically ill patients. However, new at-risk populations have emerged in recent years, such as IA associated with severe viral infections. Advanced diagnostic methods are crucial, especially considering the rising concern of antifungal resistance. Early detection is critical for successful treatment, typically involving antifungal medications like voriconazole or amphotericin B, but new antifungals are arriving to complete the therapeutic strategies. Despite advancements, mortality rates remain high, underscoring the importance of timely interventions and ongoing research. Healthcare providers should maintain a high index of suspicion, especially in immunocompromised patients and other new risk factors that are arising, to promptly diagnose and manage invasive aspergillosis.</p></span>" ] "es" => array:2 [ "titulo" => "Resumen" "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">La aspergilosis invasiva (AI) es una infección fúngica grave causada por <span class="elsevierStyleItalic">Aspergillus</span> spp., en particular <span class="elsevierStyleItalic">Aspergillus fumigatus.</span> Cada vez es más frecuente identificar otras especies, en ocasiones resistentes a los antifúngicos. La AI afecta predominantemente a pacientes inmunodeprimidos, como los pacientes con neoplasias hematológicas, receptores de trasplante de órgano sólido y los pacientes críticos. Sin embargo, en los últimos años han surgido nuevas poblaciones de riesgo, como la AI asociada a infecciones víricas graves. Los métodos de diagnóstico avanzados son cruciales, especialmente si se tiene en cuenta la creciente preocupación por la resistencia a los antifúngicos. El tratamiento suele incluir antifúngicos como el voriconazol o la anfotericina B liposomal, con nuevos antifúngicos en desarrollo que completarán las estrategias terapéuticas. A pesar de los avances, las tasas de mortalidad siguen siendo elevadas. Los profesionales sanitarios deben mantener un alto índice de sospecha, especialmente en pacientes inmunodeprimidos e identificar adecuadamente otras nuevas poblaciones en riesgo.</p></span>" ] ] "multimedia" => array:5 [ 0 => array:8 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "fuente" => "Adapted from Cadena J, Thompson GR 3rd and Patterson TF.<a class="elsevierStyleCrossRef" href="#bib0305"><span class="elsevierStyleSup">1</span></a>" "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1630 "Ancho" => 2508 "Tamanyo" => 366263 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Main risk factors for invasive aspergillosis in immunocompromised patients. AML: acute myeloid leukaemia; COPD: chronic obstructive pulmonary disease; GvHD: graft versus host disease; HSCT: haematopoietic stem cell transplantation; MDS: myelodysplastic syndrome.</p>" ] ] 1 => array:7 [ "identificador" => "fig0010" "etiqueta" => "Fig. 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 1807 "Ancho" => 3341 "Tamanyo" => 607063 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Proposed flowchart of diagnosis and therapy in invasive aspergillosis.</p>" ] ] 2 => 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:2 [ "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="elsevierStyleBold">A Host factors</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>• <span class="elsevierStyleItalic">Neutropenia (<500</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">cells/mm</span><span class="elsevierStyleSup"><span class="elsevierStyleItalic">3</span></span><span class="elsevierStyleItalic">) of at least 10 days temporally related duration.</span><span class="elsevierStyleHsp" style=""></span>• <span class="elsevierStyleItalic">Active haematological malignancy.</span><a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a><span class="elsevierStyleHsp" style=""></span>• <span class="elsevierStyleItalic">Allogeneic haematopoietic stem cell transplantation (HSCT).</span><span class="elsevierStyleHsp" style=""></span>• <span class="elsevierStyleItalic">Solid organ transplant recipients.</span><span class="elsevierStyleHsp" style=""></span>• <span class="elsevierStyleItalic">Prolonged steroid use (0.3</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">mg/kg/day prednisone</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">></span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">3 weeks).</span><span class="elsevierStyleHsp" style=""></span>• <span class="elsevierStyleItalic">T-cell immunosuppressants in the last 90 days (cyclosporine, anti-TNF-α, alemtuzumab, etc.).</span><span class="elsevierStyleHsp" style=""></span>• <span class="elsevierStyleItalic">B-cell immunosuppressants, e.g., ibrutinib.</span><span class="elsevierStyleHsp" style=""></span>• <span class="elsevierStyleItalic">Severe hereditary immunodeficiency (e.g. chronic granulomatous disease, STAT3 deficiency or severe combined immunodeficiency).</span><span class="elsevierStyleHsp" style=""></span>• <span class="elsevierStyleItalic">Acute graft-versus-host disease (GvHD) grade III/IV refractory to 1st line corticosteroid therapy.</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="elsevierStyleBold">B Clinical/radiological criteria</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>• <span class="elsevierStyleItalic"><span class="elsevierStyleBold">Pulmonary aspergillosis:</span> The presence of at least 1 of the following radiological patterns on CT:</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>1) Nodule(s), with or without halo sign.<span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>2) Crescent or crescent air sign.<span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>3) Cavitation.<span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>4) Segmental or lobar wedge consolidation.<span class="elsevierStyleHsp" style=""></span>• <span class="elsevierStyleItalic"><span class="elsevierStyleBold">Tracheobronchitis:</span> Bronchoscopy</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">→</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">ulcers, nodules, pseudo-membranes, plaques or eschar.</span><span class="elsevierStyleHsp" style=""></span>• <span class="elsevierStyleItalic"><span class="elsevierStyleBold">Sinusitis:</span> Requires CT scan and ≥1 of the following:</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>1) acute localised pain (including pain radiating to the eye).<span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>2) nasal ulcer with black crust.<span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>3) extension to bone or orbit.<span class="elsevierStyleHsp" style=""></span>• <span class="elsevierStyleItalic"><span class="elsevierStyleBold">CNS infection:</span> On CT/MRI at least 1 of the following signs:</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>1) focal lesions.<span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>2) meningeal enhancement. \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="elsevierStyleBold">C Microbiology criteria</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>• <span class="elsevierStyleItalic">Any Aspergillus isolated by culture from sputum, BALf, bronchial or tracheal aspirate.</span><span class="elsevierStyleHsp" style=""></span>• <span class="elsevierStyleItalic">Direct view of hyphae with calcofluor stain under the microscope.</span><span class="elsevierStyleHsp" style=""></span>• <span class="elsevierStyleItalic">Aspergillus antigen or galactomannan (GM) at least 1 of the following:</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>1) Serum<span class="elsevierStyleHsp" style=""></span>≥<span class="elsevierStyleHsp" style=""></span>1.0<a class="elsevierStyleCrossRef" href="#tblfn0010"><span class="elsevierStyleSup">b</span></a> (one sample).<span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>2) BALf<span class="elsevierStyleHsp" style=""></span>≥<span class="elsevierStyleHsp" style=""></span>1.0.<a class="elsevierStyleCrossRef" href="#tblfn0010"><span class="elsevierStyleSup">b</span></a><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>3) Serum<span class="elsevierStyleHsp" style=""></span>≥<span class="elsevierStyleHsp" style=""></span>0.7<a class="elsevierStyleCrossRef" href="#tblfn0010"><span class="elsevierStyleSup">b</span></a> and LBA<span class="elsevierStyleHsp" style=""></span>≥<span class="elsevierStyleHsp" style=""></span>0.8.<a class="elsevierStyleCrossRef" href="#tblfn0010"><span class="elsevierStyleSup">b</span></a><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>4) CSF<span class="elsevierStyleHsp" style=""></span>≥<span class="elsevierStyleHsp" style=""></span>1.0.<a class="elsevierStyleCrossRef" href="#tblfn0010"><span class="elsevierStyleSup">b</span></a><span class="elsevierStyleHsp" style=""></span>• <span class="elsevierStyleItalic">Molecular (PCR): at least 1 of the following:</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>1) Plasma, serum or whole blood: 2 or more consecutive positive PCRs.<span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>2) BALf: 2 or more duplicate positive PCR.<span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>3) At least 1 positive PCR positive in plasma, serum or whole blood and 1 positive PCR in BALf. \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab3627856.png" ] ] ] "notaPie" => array:2 [ 0 => array:3 [ "identificador" => "tblfn0005" "etiqueta" => "a" "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Haematological malignancy refers to active malignancy, in receipt of treatment for this malignancy, and those in remission in the recent past. These patients would comprise largely acute leukemias and lymphomas, as well as multiple myeloma, whereas patients with aplastic anaemia represent a more heterogeneous group of individuals and are not included.</p>" ] 1 => array:3 [ "identificador" => "tblfn0010" "etiqueta" => "b" "nota" => "<p class="elsevierStyleNotepara" id="npar0010">Recommended cut-off points for diagnosis with Platelia (Bio-Rad) ELISA test.</p> <p class="elsevierStyleNotepara" id="npar0015">BALf: bronchoalveolar lavage fluid; CSF: cerebrospinal fluid; CT: computed tomography; MRI: magnetic resonance imaging; PCR: polymerase chain reaction.</p>" ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">European Organization for Research and Treatment of Cancer and the Mycoses Study Group Education and Research Consortium (EORTC/MSGERC) 2019 updated criteria.<a class="elsevierStyleCrossRef" href="#bib0465"><span class="elsevierStyleSup">33</span></a></p>" ] ] 3 => 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:2 [ "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="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Antifungal agent \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">Loading dose \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">Maintenance \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" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " colspan="3" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">Triazoles</span></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>Voriconazole \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">IV: 6<span class="elsevierStyleHsp" style=""></span>mg/kg/12<span class="elsevierStyleHsp" style=""></span>h (Day 1)Oral: 400<span class="elsevierStyleHsp" style=""></span>mg/12 (Day 1) \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">4<span class="elsevierStyleHsp" style=""></span>mg/kg/12<span class="elsevierStyleHsp" style=""></span>h200<span class="elsevierStyleHsp" style=""></span>mg/12<span class="elsevierStyleHsp" style=""></span>h \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>Isavuconazole \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">IV or oral:200<span class="elsevierStyleHsp" style=""></span>mg/8<span class="elsevierStyleHsp" style=""></span>h (Days 1–2) \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">200<span class="elsevierStyleHsp" style=""></span>mg/24<span class="elsevierStyleHsp" style=""></span>h \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>Posaconazole \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">IV or oral:300<span class="elsevierStyleHsp" style=""></span>mg/12<span class="elsevierStyleHsp" style=""></span>h (Day 1) \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">300<span class="elsevierStyleHsp" style=""></span>mg/24<span class="elsevierStyleHsp" style=""></span>h \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " colspan="3" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " colspan="3" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">Polyenes</span></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>Liposomal amphotericin B<a class="elsevierStyleCrossRef" href="#tblfn0015"><span class="elsevierStyleSup">a</span></a> \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">– \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">IV: 3<span class="elsevierStyleHsp" style=""></span>mg/kg/24<span class="elsevierStyleHsp" style=""></span>h \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " colspan="3" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " colspan="3" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">Echinocandins</span><a class="elsevierStyleCrossRef" href="#tblfn0020"><span class="elsevierStyleSup">b</span></a></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>Caspofungin \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">IV: 70<span class="elsevierStyleHsp" style=""></span>mg (Day 1) \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">50<span class="elsevierStyleHsp" style=""></span>mg/24<span class="elsevierStyleHsp" style=""></span>h \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>Micafungin \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">– \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">IV: 100<span class="elsevierStyleHsp" style=""></span>mg/24<span class="elsevierStyleHsp" style=""></span>h \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>Anidulafungin \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">IV: 200<span class="elsevierStyleHsp" style=""></span>mg (Day 1) \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<span class="elsevierStyleHsp" style=""></span>mg/24<span class="elsevierStyleHsp" style=""></span>h \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab3627855.png" ] ] ] "notaPie" => array:2 [ 0 => array:3 [ "identificador" => "tblfn0015" "etiqueta" => "a" "nota" => "<p class="elsevierStyleNotepara" id="npar0020">Higher dosage could be necessary depending on site of infection (p.e. CNS).</p>" ] 1 => array:3 [ "identificador" => "tblfn0020" "etiqueta" => "b" "nota" => "<p class="elsevierStyleNotepara" id="npar0025">Not recommended in monotherapy.</p>" ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Dosage for antifungals in invasive aspergillosis.</p>" ] ] 4 => array:8 [ "identificador" => "tbl0015" "etiqueta" => "Table 3" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at3" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">IA: invasive aspergillosis, ICU: intensive care unit, IPA: invasive pulmonary aspergillosis, IV: intravenous, L-AmB: liposomal amphotericin B.</p>" "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><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">Mechanism of action \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">Formulation \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">Spectrum in IA \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">Future role in IA \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">Fosmanogepix \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">A novel Gwt1 enzyme inhibitor, essential for anchoring mannoproteins to the fungal cell membrane and wall. \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">Oral and IV \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">Broad spectrum, including azole-resistant <span class="elsevierStyleItalic">A. fumigatus</span>. \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">Probable alternative to azoles to treat IA in monotherapy or in combination with L-AmB in these contexts. \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">Ibrexafungerp \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">First-in-class triterpenoid. Similar mechanisms than echinocandins, inhibiting the biosynthesis of BDG in the fungal cell wall. \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">Oral (IV on pre-clinical phases) \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">Fungistatic action against on <span class="elsevierStyleItalic">Aspergillus</span> spp., including cryptic species and those azole-resistant. \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">Ongoing clinical trials in combination therapy. \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">Olorofim \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">First clinical compound from the novel antifungal class of the orotomides. Its mechanism is based on the inhibition of the dihydroorotate dehydrogenase. \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">Oral and IV \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">Active against several mould difficult-to-treat infections, including <span class="elsevierStyleItalic">Aspergillus</span> cryptic species and azole-resistant <span class="elsevierStyleItalic">Aspergillus fumigatus</span>. \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">Alternative to azoles, especially azole-resistant IA. \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">Opelconazole \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">Novel antifungal triazole optimised for inhalation.Low potential systemic adverse drug effects and drug–drug interactions \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">Inhaled \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">Similar to other systemic triazoles (in vitro studies).No activity against <span class="elsevierStyleItalic">A. niger.</span> \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">IPA in non-neutropenic patients without dissemination, in combination therapy approaches.Antifungal prophylaxis after lung transplantation and in the ICU setting (high concentration in the airways). \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">Rezafungin \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">A new echinocandin designed to be dosed once weekly. Analogue to anidulafungin but with a structural modification that results in a longer half-life. \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">IV \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">The activity against <span class="elsevierStyleItalic">Aspergillus</span> spp. is comparable to other echinocandins, being active also against cryptic and azole-resistant. \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">Ongoing clinical trial of rezafungin for prevention of invasive fungal infections (including <span class="elsevierStyleItalic">Candida</span> spp., <span class="elsevierStyleItalic">Aspergillus</span> spp., and <span class="elsevierStyleItalic">P. jirovecii</span>) in patients undergoing allogeneic stem-cell transplant. \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab3627854.png" ] ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">New antifungals for invasive aspergillosis therapy.</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0015" "bibliografiaReferencia" => array:60 [ 0 => array:3 [ "identificador" => "bib0305" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Invasive aspergillosis: current strategies for diagnosis and management" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "J. 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