Review
Pulmonary complications of malaria: An update
Actualización de las complicaciones pulmonares de la malaria
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Esta especie es la responsable de la mayoría de las complicaciones pulmonares de la malaria.</p>" ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Itxasne Cabezón Estévanez, Miguel Górgolas Hernández-Mora" "autores" => array:2 [ 0 => array:2 [ "nombre" => "Itxasne" "apellidos" => "Cabezón Estévanez" ] 1 => array:2 [ "nombre" => "Miguel" "apellidos" => "Górgolas Hernández-Mora" ] ] ] ] ] "idiomaDefecto" => "es" "Traduccion" => array:1 [ "en" => array:9 [ "pii" => "S2387020616302960" "doi" => "10.1016/j.medcle.2016.06.017" "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/S2387020616302960?idApp=UINPBA00004N" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0025775316000129?idApp=UINPBA00004N" "url" => "/00257753/0000014600000008/v1_201604080141/S0025775316000129/v1_201604080141/es/main.assets" ] ] "itemSiguiente" => array:19 [ "pii" => "S2387020616302893" "issn" => "23870206" "doi" => "10.1016/j.medcle.2016.06.010" "estado" => "S300" "fechaPublicacion" => "2016-04-15" "aid" => "3465" "copyright" => "Elsevier España, S.L.U." 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(1) <span class="elsevierStyleItalic">Homo sapiens</span> (sp. | P17813 # 1); (2) <span class="elsevierStyleItalic">Homo sapiens</span> mutated (sp. | P17813 # 1); (3) <span class="elsevierStyleItalic">Mus musculus</span> (sp. | Q63961 # 1); (4) <span class="elsevierStyleItalic">Rattus norvegicus</span> (sp. | Q6Q3E8 # 1); (5) <span class="elsevierStyleItalic">Macaca mulatta</span> (sp. | F7BB68 # 1); (6) <span class="elsevierStyleItalic">Sus scrofa</span> (sp. | P37176 # 1); (7) <span class="elsevierStyleItalic">Oryctolagus cuniculus</span> (sp. | G1SSF2 # 1); (8) <span class="elsevierStyleItalic">Canis familiaris</span> (sp. | F1P847 # 1); (9) <span class="elsevierStyleItalic">Bos taurus</span> (sp. | Q1RMV1 # 1); (10) <span class="elsevierStyleItalic">Equus</span> (sp. | W046 F6 # 1); (11) <span class="elsevierStyleItalic">Loxodonta africana</span> (sp. | G3SR82 # 1); (12): <span class="elsevierStyleItalic">Ailuropoda melanoleuca</span> (sp. | G1 M9D6 # 1).</p>" ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Guillermo Pousada, Adolfo Baloira, Olalla Castro-Añón, Diana Valverde" "autores" => array:4 [ 0 => array:2 [ "nombre" => "Guillermo" "apellidos" => "Pousada" ] 1 => array:2 [ "nombre" => "Adolfo" "apellidos" => "Baloira" ] 2 => array:2 [ "nombre" => "Olalla" "apellidos" => "Castro-Añón" ] 3 => array:2 [ "nombre" => "Diana" "apellidos" => "Valverde" ] ] ] ] ] "idiomaDefecto" => "en" "Traduccion" => array:1 [ "es" => array:9 [ "pii" => "S0025775316000117" "doi" => "10.1016/j.medcli.2015.12.014" "estado" => "S300" "subdocumento" => "" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:1 [ "total" => 0 ] "idiomaDefecto" => "es" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0025775316000117?idApp=UINPBA00004N" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2387020616302972?idApp=UINPBA00004N" "url" => "/23870206/0000014600000008/v1_201607210236/S2387020616302972/v1_201607210236/en/main.assets" ] "en" => array:21 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Review</span>" "titulo" => "Pulmonary complications of malaria: An update" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "354" "paginaFinal" => "358" ] ] "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "Itxasne Cabezón Estévanez, Miguel Górgolas Hernández-Mora" "autores" => array:2 [ 0 => array:4 [ "nombre" => "Itxasne" "apellidos" => "Cabezón Estévanez" "email" => array:1 [ 0 => "itxascabezon@yahoo.es" ] "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">*</span>" "identificador" => "cor0005" ] ] ] 1 => array:3 [ "nombre" => "Miguel" "apellidos" => "Górgolas Hernández-Mora" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0010" ] ] ] ] "afiliaciones" => array:2 [ 0 => array:3 [ "entidad" => "Servicio de Medicina Interna, Hospital Universitario de Cruces, Baracaldo, Vizcaya, Spain" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Servicio de Enfermedades Infecciosas, Fundación Jiménez Díaz, Madrid, Spain" "etiqueta" => "b" "identificador" => "aff0010" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Actualización de las complicaciones pulmonares de la malaria" ] ] "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" => 858 "Ancho" => 1025 "Tamanyo" => 77626 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Chest X-ray of a patient with acute respiratory distress syndrome in a case of severe malaria caused by <span class="elsevierStyleItalic">Plasmodium falciparum</span>. Respiratory symptoms began 72<span class="elsevierStyleHsp" style=""></span>h after parenteral antimalarial treatment initiation.</p>" ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Malaria is an infectious disease transmitted by the <span class="elsevierStyleItalic">Anopheles</span> spp. female mosquito and produced by 5 species of the <span class="elsevierStyleItalic">Plasmodium parasite</span>: <span class="elsevierStyleItalic">Plasmodium falciparum</span> (<span class="elsevierStyleItalic">P. falciparum</span>), <span class="elsevierStyleItalic">Plasmodium vivax</span> (<span class="elsevierStyleItalic">P. vivax</span>), <span class="elsevierStyleItalic">Plasmodium ovale</span> (<span class="elsevierStyleItalic">P. ovale</span>), <span class="elsevierStyleItalic">Plasmodium malariae</span> and <span class="elsevierStyleItalic">Plasmodium knowlesi</span> (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>). It is a global public health problem, especially in the tropics and subtropics, as reflected in the estimates made in 2015 by the World Health Organization (WHO): 3.2 billion people in 97 countries at risk of contracting the disease, 214 million cases and 438,000 deaths. It is the tropical disease with the highest number of fatalities, most of them occurring in children under 5 and pregnant women in Africa.<a class="elsevierStyleCrossRefs" href="#bib0175"><span class="elsevierStyleSup">1,2</span></a></p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0010" class="elsevierStylePara elsevierViewall">Complications of malaria are often subject to study, not so much for its frequency as its high mortality (up to 30% despite a correct treatment). Whenever there is evidence of organ dysfunction, either by clinical data or by laboratory data, it is called severe or complicated malaria. The most common clinical signs and symptoms are cerebral malaria, renal failure and metabolic acidosis, but 2 pulmonary manifestations are also included in its definition: pulmonary oedema and acute respiratory distress syndrome (ARDS).<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">3</span></a> Most cases of ARDS occurring in malaria patients are, like the rest of complications, secondary to <span class="elsevierStyleItalic">P. falciparum</span> species infection, but cases have been reported in all species.<a class="elsevierStyleCrossRefs" href="#bib0190"><span class="elsevierStyleSup">4–10</span></a></p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Epidemiology</span><p id="par0015" class="elsevierStylePara elsevierViewall">The incidence of pulmonary complications of malaria has increased in recent decades, being more frequent in non-immune patients between 20 and 40 years of age and in situations of delayed treatment (after the seventh day from symptoms onset). A 4–18% of adult patients with <span class="elsevierStyleItalic">P. falciparum</span> malaria present with respiratory symptoms and post-mortem studies in non-immune patients reveal that 21–23% develop pulmonary oedema. Regarding ARDS, an incidence of 5–25% is estimated in the case of <span class="elsevierStyleItalic">P. falciparum</span> and 1–10% in <span class="elsevierStyleItalic">P. vivax</span>.<a class="elsevierStyleCrossRefs" href="#bib0180"><span class="elsevierStyleSup">2,11</span></a> Advanced age, immunosuppression and pregnancy are risk factors for developing this entity.<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">7</span></a></p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Physiopathogeny</span><p id="par0020" class="elsevierStylePara elsevierViewall">The essential pathogenesis of malaria is the parasite invasion of red blood cells with the subsequent development of anaemia due to both, haemolysis as well as splenic sequestration of the parasitized red blood cells. Parasitic destruction releases toxins that cause endothelial damage and activate proinflammatory cytokines such as interleukin (IL)-1, 6 and 12 occurs, the <span class="elsevierStyleItalic">tumour necrosis factor</span> (TNF)α and platelet activating factor; these cytokines promote cell adhesion (parasitized red blood cells, leucocytes and platelets) to the endothelium, causing tissue hypoxia.<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">12</span></a></p><p id="par0025" class="elsevierStylePara elsevierViewall">By extrapolation from studies in cerebral malaria, it is considered that serious forms of malaria are secondary to hypoxia due to occlusion of the microvasculature of vital organs by parasitized red blood cells. These RBCs also adhere together to form structures called “rosettes” contributing to a reduced circulatory flow and multiorgan dysfunction.<a class="elsevierStyleCrossRefs" href="#bib0230"><span class="elsevierStyleSup">12,13</span></a></p><p id="par0030" class="elsevierStylePara elsevierViewall">Regarding the pulmonary complications, it appears that the endothelial damage is multifactorial:<ul class="elsevierStyleList" id="lis0005"><li class="elsevierStyleListItem" id="lsti0005"><span class="elsevierStyleLabel">a)</span><p id="par0035" class="elsevierStylePara elsevierViewall">Development of an intense inflammatory response by activation of inflammatory cells and cytokines. An imbalance occurs in the production of cytokines, with proinflammatory being predominant versus antiinflammatory.<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">14</span></a></p></li><li class="elsevierStyleListItem" id="lsti0010"><span class="elsevierStyleLabel">b)</span><p id="par0040" class="elsevierStylePara elsevierViewall">Pulmonary accumulation of monocytes and intravascular inflammatory changes.<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">6</span></a></p></li><li class="elsevierStyleListItem" id="lsti0015"><span class="elsevierStyleLabel">c)</span><p id="par0045" class="elsevierStylePara elsevierViewall">“Extrapulmonary” factors: treatment with quinine, thrombocytopenia, patient's immune response, formation of “rosettes” (<span class="elsevierStyleItalic">P. falciparum</span>), decreased production of nitric oxide.<a class="elsevierStyleCrossRefs" href="#bib0245"><span class="elsevierStyleSup">15–17</span></a></p></li></ul></p><p id="par0050" class="elsevierStylePara elsevierViewall">Some authors argue that the origin of endothelial damage in ARDS varies depending on the <span class="elsevierStyleItalic">Plasmodium</span> species: while in the case of <span class="elsevierStyleItalic">P. falciparum</span> the cause seems to be the same as in other complications (microvascular endothelium obstruction due to adhesion of the parasitized red blood cells), in other species this seems to have a minor role.<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">14</span></a> Thus, in <span class="elsevierStyleItalic">P. vivax</span> and <span class="elsevierStyleItalic">P. ovale</span> infections, endothelial damage is primarily caused by an post-treatment inflammatory response induced by parasite death and capillary reperfusion, with the release of soluble mediators (proinflammatory cytokines and parasitic antigens).<a class="elsevierStyleCrossRefs" href="#bib0220"><span class="elsevierStyleSup">10,18</span></a> Among the cytokines, TNFα appears to have a predominant role in the pathogenesis of pulmonary oedema: firstly, it induces neutrophil hyper-adhesion to the endothelium (by expression of adhesion molecules on the cell surface, particularly ICAM-1), and secondly, alters the expression of the sodium channels, thus increasing epithelial and endothelial permeability.<a class="elsevierStyleCrossRefs" href="#bib0240"><span class="elsevierStyleSup">14,19</span></a> In any case, endothelial dysfunction is a disruption of the alveolar-capillary barrier integrity, allowing the passage of proteins into the interstitium with an increase in interstitial pressure that causes the passage of fluids to the alveolar space. This is a non-cardiogenic pulmonary oedema, sometimes aggravated by hypoalbuminaemia and fluid overload often present in patients with malaria.<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">11</span></a></p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Clinical signs and symptoms</span><p id="par0055" class="elsevierStylePara elsevierViewall">Pulmonary involvement in malaria can be asymptomatic or oligosymptomatic. 20–50% of patients with malaria have dry cough. Sometimes they present with tachypnoea, which may be due to fever, anaemia or lung disease. Pneumonitis is rare, −1.5% in some series,<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">4</span></a> and some authors suggest that it is due to intercurrent pneumonia, pulmonary oedema or the existence of metabolic acidosis.<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">15</span></a> There have been reports of interstitial pneumonia caused by <span class="elsevierStyleItalic">P. vivax</span>.<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">20</span></a></p><p id="par0060" class="elsevierStylePara elsevierViewall">The most feared complication is the development of severe respiratory insufficiency due to an increased alveolar permeability, known as respiratory distress. When a number of criteria are met, it is called ARDS, a serious multifactorial aetiology entity (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>). Although its clinical presentation may vary depending on the causal species of <span class="elsevierStyleItalic">Plasmodium</span> (<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>), the typical clinical features of ARDS consists of sudden dyspnoea, coughing and severe hypoxia, which can be refractory to oxygen therapy and compromise the patient's life. Often accompanied by agitation and disorientation, which may be due to hypoxia itself or concomitant cerebral malaria. On physical examination, tachypnoea is usually the earliest sign, followed by central and peripheral cyanosis, bibasilar crackles and expiratory wheezing.<a class="elsevierStyleCrossRefs" href="#bib0180"><span class="elsevierStyleSup">2,21</span></a></p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><elsevierMultimedia ident="tbl0010"></elsevierMultimedia></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Diagnosis</span><p id="par0065" class="elsevierStylePara elsevierViewall">In all patients with uncomplicated malaria the presence of <span class="elsevierStyleItalic">P. falciparum</span> (alone or in co-infection) should be ruled out exhaustively. The <span class="elsevierStyleItalic">gold standard</span> diagnostic method in malaria is parasite visualization in the thick film and the peripheral blood smear. If a microscope is not available or false negatives are suspected (when the patient has received incomplete antimalarial treatment) immunochromatographic antigen detection tests that are simple and quick to perform can be used. These have a 90% sensitivity (approx.). However, these tests do not replace the smear and the thick film, as they have false negatives and do not allow to quantify parasitaemia.<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">3</span></a></p><p id="par0070" class="elsevierStylePara elsevierViewall">The diagnosis of ARDS is based on clinical history and physical examination, performing an arterial blood gas test (showing hypoxaemia and, sometimes, metabolic acidosis) and a simple chest radiography, showing evidence of bilateral alveolar infiltrates with normal cardiac silhouette (except in cases with concomitant disease) (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>); pleural effusion and thickening of fissures are rare finds. Malaria should be ruled out in all patients with respiratory distress residing in an endemic area or coming from it. The presence of a radiographic infiltrates in these patients with distress does not rule out the diagnosis of malaria, since up to 13% have concomitant pneumonia.<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">2</span></a></p><elsevierMultimedia ident="fig0010"></elsevierMultimedia></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Treatment</span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">General supportive measures</span><p id="par0075" class="elsevierStylePara elsevierViewall">Patients who develop ARDS are at high risk of mortality and must be admitted to an intensive care unit (ICU), with continuous monitoring of systemic and pulmonary arterial blood pressure, arterial oxygen saturation, glucose and diuresis.<a class="elsevierStyleCrossRef" href="#bib0305"><span class="elsevierStyleSup">27</span></a> If an ICU unit is not available, the aim of the centre should be to stabilize the patient from a respiratory and haemodynamic standpoint (see below) while a transfer to a tertiary hospital is prepared, in addition to initiating the already mentioned monitoring. If no specialized units are available, as it is the case in many regions of the tropics and subtropics, at least the temperature, heart rate, blood pressure and level of consciousness should be monitored.<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">3</span></a> All possible reversible causes of distress (acidosis, anaemia) should be corrected and primary prophylaxis of venous thromboembolism and gastrointestinal bleeding should be established. In order to prevent catheter-associated infections, enteral nutrition is preferable.<a class="elsevierStyleCrossRefs" href="#bib0180"><span class="elsevierStyleSup">2,11</span></a> There is insufficient evidence to recommend standardized use of corticosteroids, mannitol or exchange transfusion.</p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Fluid therapy</span><p id="par0080" class="elsevierStylePara elsevierViewall">Knowledge of the use of fluids in ARDS has improved considerably in recent years, and a “conservative” strategy is now recommended (to reduce fluid intake and force a negative hydration balance), which decreases the incidence of pulmonary oedema, multiorgan failure and hospital stay.<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">2</span></a> WHO recommends the use of glucose 5% or saline 0.9% at a rate of 3–4<span class="elsevierStyleHsp" style=""></span>ml/kg/h in the paediatric population and 1–2<span class="elsevierStyleHsp" style=""></span>ml/kg/h in adults.<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">3</span></a> If necessary, crystalloids and vasopressors should be used (such as dopamine) to maintain a central venous pressure of 8–12<span class="elsevierStyleHsp" style=""></span>mmHg, avoiding the use of adrenaline due to its ability to produce lactic acidosis.<a class="elsevierStyleCrossRefs" href="#bib0225"><span class="elsevierStyleSup">11,26</span></a> Loop diuretics, venodilators, opiates and even haemofiltration or dialysis should be used when facing with elevated venous pressures in order to optimize cardiac output.</p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Ventilatory support</span><p id="par0085" class="elsevierStylePara elsevierViewall">Mechanical ventilation strategies are the same as in ARDS due to other causes, except permissive hypercapnia, since carbon dioxide (CO<span class="elsevierStyleInf">2</span>) increases cerebral blood flow and thus intracranial pressure, which has a deleterious effect in patients with malaria and altered level of consciousness.<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">5</span></a> The mask can be used as an initial respiratory support with FiO<span class="elsevierStyleInf">2</span> flow of 0.5–0.6 or non-invasive type mechanical ventilation <span class="elsevierStyleItalic">continuous positive airway pressure</span> (CPAP, “continuous positive airway pressure”) or positive pressure of 2 levels in the airway; some authors have shown a better outcome with the latter in ARDS caused by <span class="elsevierStyleItalic">P. vivax</span>.<a class="elsevierStyleCrossRef" href="#bib0310"><span class="elsevierStyleSup">28</span></a> Invasive mechanical ventilation should be assessed in the following cases:<ul class="elsevierStyleList" id="lis0010"><li class="elsevierStyleListItem" id="lsti0020"><span class="elsevierStyleLabel">a)</span><p id="par0090" class="elsevierStylePara elsevierViewall">Patient with altered level of consciousness.</p></li><li class="elsevierStyleListItem" id="lsti0025"><span class="elsevierStyleLabel">b)</span><p id="par0095" class="elsevierStylePara elsevierViewall">Need for FiO<span class="elsevierStyleInf">2</span> greater than 0.6 (or pressures higher than 10<span class="elsevierStyleHsp" style=""></span>cmH<span class="elsevierStyleInf">2</span>O in the CPAP) to maintain a PaO<span class="elsevierStyleInf">2</span> over 60<span class="elsevierStyleHsp" style=""></span>mmHg.<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">7</span></a></p></li></ul></p><p id="par0100" class="elsevierStylePara elsevierViewall">An Inspiratory: Expiratory time ratio of 1:1 or 2:1 is recommended. FiO<span class="elsevierStyleInf">2</span> and positive pressure at the end of expiration should be adjusted to maintain adequate blood oxygenation. Protective lung ventilation (initial tidal volume of 6<span class="elsevierStyleHsp" style=""></span>ml/kg) and a maximum plateau pressure of 30<span class="elsevierStyleHsp" style=""></span>cmH<span class="elsevierStyleInf">2</span>O improve prognosis.<a class="elsevierStyleCrossRef" href="#bib0315"><span class="elsevierStyleSup">29</span></a></p><p id="par0105" class="elsevierStylePara elsevierViewall">Extracorporeal membrane oxygenation (ECMO) is a circuit that directly oxygenates the blood while eliminating CO<span class="elsevierStyleInf">2</span>, improving gas exchange and accelerating lung tissue healing. Its use may be considered in refractory cases of ARDS in which positive pressure ventilation is not able to maintain adequate gas exchange or when an unacceptable hypercapnia occurs.<a class="elsevierStyleCrossRef" href="#bib0320"><span class="elsevierStyleSup">30</span></a> Experience with ECMO in malaria is limited, and available data refer to case series where it has been observed that a low tidal volume (<6<span class="elsevierStyleHsp" style=""></span>ml/kg) and low oxygen concentrations can be maintained, reducing lung damage associated with ventilation.<a class="elsevierStyleCrossRef" href="#bib0325"><span class="elsevierStyleSup">31</span></a> It also exercises strict control of CO<span class="elsevierStyleInf">2</span> blood pressure, preventing increased intracranial pressure.<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">5</span></a> Despite its benefits, ECMO is not without risks and there are no uniform criteria for use in ARDS, so Alves et al. recommend using it only in cases of ARDS refractory to other measures.<a class="elsevierStyleCrossRef" href="#bib0325"><span class="elsevierStyleSup">31</span></a> Ventral decubitus, in turn, increases the oxygenation but does not improve survival.<a class="elsevierStyleCrossRef" href="#bib0330"><span class="elsevierStyleSup">32</span></a></p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Antimalarial agents</span><p id="par0110" class="elsevierStylePara elsevierViewall">All patients with confirmed severe malaria should receive early parenteral antimalarial treatment. The drug of choice, both in adults as well as in children/pregnant women, is intravenous artesunate; randomized studies have shown to decrease mortality by 35% in adults and 22% in children compared with quinine.<a class="elsevierStyleCrossRefs" href="#bib0180"><span class="elsevierStyleSup">2,33</span></a> The initial dose is 2.4<span class="elsevierStyleHsp" style=""></span>mg/kg/12<span class="elsevierStyleHsp" style=""></span>h (2 doses) followed by 2.4<span class="elsevierStyleHsp" style=""></span>mg/kg/d. If artesunate is not available, intravenous quinine can be used, bearing in mind its most common side effects: hypoglycaemia and arrhythmias. In the tropics, there is usually increased availability of intramuscular artemether, but absorption is erratic, so its use should be avoided. Treatment should be administered parenterally for at least 24<span class="elsevierStyleHsp" style=""></span>h. Subsequently, if the clinical progression is favourable, the thick blood film becomes negative and the patient shows good oral tolerance, therefore, an oral treatment can be initiated, preferably with artemisinin-based combinations.<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">3</span></a></p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Antibiotic treatment</span><p id="par0115" class="elsevierStylePara elsevierViewall">0.2–13% of malaria patients have concomitant bacteraemia, being the most severe forms the most likely to suffer bacterial infections.<a class="elsevierStyleCrossRef" href="#bib0340"><span class="elsevierStyleSup">34</span></a> Some authors suggest that bacterial sepsis has a role in the pathogenesis of ARDS, proposing to initiate broad-spectrum antibiotic therapy in all patients with malaria who develop this entity.<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">11</span></a> The WHO, meanwhile, recommends the use of antibiotics in all paediatric patients with altered level of consciousness to rule out bacterial infection, and adults who present hypotension or radiological infiltrates. The predominant infections in these patients are caused by respiratory pathogens (pneumococcus and <span class="elsevierStyleItalic">Haemophilus influenzae</span>) and enterobacteria, so a good option would be the use of third-generation cephalosporins.<a class="elsevierStyleCrossRefs" href="#bib0180"><span class="elsevierStyleSup">2,3</span></a></p></span></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Prognosis</span><p id="par0120" class="elsevierStylePara elsevierViewall">The development of ARDS is a predictor of mortality in malaria.<a class="elsevierStyleCrossRefs" href="#bib0195"><span class="elsevierStyleSup">5,34</span></a> 40% of patients die despite appropriate treatment, and 80–100% without ventilatory support.<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">2</span></a> The prognosis worsens when the causative agent is <span class="elsevierStyleItalic">P. falciparum</span>, given its frequent association with other complications.<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">11</span></a></p></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Conclusion</span><p id="par0125" class="elsevierStylePara elsevierViewall">Pulmonary forms of severe malaria have experienced an increased incidence in recent years. ARDS is the most severe clinical form because it has a poor prognosis despite appropriate treatment. If this entity is clinically suspected, ventilatory and haemodynamic support and parenteral antimalarial treatment should be initiated at an early stage, preferably in an ICU.</p></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Conflict of interests</span><p id="par0130" class="elsevierStylePara elsevierViewall">The authors declare no conflict of interest.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:15 [ 0 => array:3 [ "identificador" => "xres694961" "titulo" => "Abstract" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0005" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec704729" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres694960" "titulo" => "Resumen" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0010" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec704730" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:2 [ "identificador" => "sec0010" "titulo" => "Epidemiology" ] 6 => array:2 [ "identificador" => "sec0015" "titulo" => "Physiopathogeny" ] 7 => array:2 [ "identificador" => "sec0020" "titulo" => "Clinical signs and symptoms" ] 8 => array:2 [ "identificador" => "sec0025" "titulo" => "Diagnosis" ] 9 => array:3 [ "identificador" => "sec0030" "titulo" => "Treatment" "secciones" => array:5 [ 0 => array:2 [ "identificador" => "sec0035" "titulo" => "General supportive measures" ] 1 => array:2 [ "identificador" => "sec0040" "titulo" => "Fluid therapy" ] 2 => array:2 [ "identificador" => "sec0045" "titulo" => "Ventilatory support" ] 3 => array:2 [ "identificador" => "sec0050" "titulo" => "Antimalarial agents" ] 4 => array:2 [ "identificador" => "sec0055" "titulo" => "Antibiotic treatment" ] ] ] 10 => array:2 [ "identificador" => "sec0060" "titulo" => "Prognosis" ] 11 => array:2 [ "identificador" => "sec0065" "titulo" => "Conclusion" ] 12 => array:2 [ "identificador" => "sec0070" "titulo" => "Conflict of interests" ] 13 => array:2 [ "identificador" => "xack232408" "titulo" => "Acknowledgements" ] 14 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2015-10-13" "fechaAceptado" => "2015-11-26" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec704729" "palabras" => array:4 [ 0 => "Malaria" 1 => "Acute respiratory distress syndrome" 2 => "<span class="elsevierStyleItalic">Plasmodium falciparum</span>" 3 => "Mortality" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec704730" "palabras" => array:4 [ 0 => "Paludismo" 1 => "Síndrome de distrés respiratorio agudo" 2 => "<span class="elsevierStyleItalic">Plasmodium falciparum</span>" 3 => "Mortalidad" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Malaria is the most important parasitic disease worldwide, being a public health challenge in more than 90 countries. The incidence of pulmonary manifestations has increased in recent years. Acute respiratory distress syndrome is the most severe form within the pulmonary complications of malaria, with high mortality despite proper management. This syndrome manifests with sudden dyspnoea, cough and refractory hypoxaemia. Patients should be admitted to intensive care units and treated with parenteral antimalarial drug treatment and ventilatory and haemodynamic support without delay. Therefore, dyspnoea in patients with malaria should alert clinicians, as the development of respiratory distress is a poor prognostic factor.</p></span>" ] "es" => array:2 [ "titulo" => "Resumen" "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">La malaria es, globalmente, la enfermedad parasitaria más importante, representando un problema de salud pública en más de 90 países. En los últimos años se ha observado un aumento en la incidencia de las complicaciones pulmonares. Su forma clínica más grave es el síndrome de distrés respiratorio agudo, que tiene una elevada mortalidad a pesar de un adecuado abordaje terapéutico. Se presenta como un cuadro de disnea súbita, tos e hipoxemia refractaria, requiriendo ingreso en unidades de cuidados intensivos, tratamiento antipalúdico parenteral precoz, y soporte ventilatorio y hemodinámico. Todo paciente con malaria que presente disnea requiere vigilancia estrecha, ya que el desarrollo de distrés respiratorio es un factor de mal pronóstico.</p></span>" ] ] "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "<p class="elsevierStyleNotepara" id="npar0020">Please cite this article as: Cabezón Estévanez I, Górgolas Hernández-Mora M. Actualización de las complicaciones pulmonares de la malaria. Med Clin (Barc). 2016;146:354–358.</p>" ] ] "multimedia" => array:4 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 672 "Ancho" => 1025 "Tamanyo" => 91941 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Peripheral blood smear stained with Giemsa where multiple parasitism by <span class="elsevierStyleItalic">Plasmodium falciparum</span> trophozoites of a red blood cell is observed. This species is responsible for most of the pulmonary complications of malaria.</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" => 858 "Ancho" => 1025 "Tamanyo" => 77626 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Chest X-ray of a patient with acute respiratory distress syndrome in a case of severe malaria caused by <span class="elsevierStyleItalic">Plasmodium falciparum</span>. Respiratory symptoms began 72<span class="elsevierStyleHsp" style=""></span>h after parenteral antimalarial treatment initiation.</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:3 [ "leyenda" => "<p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">ARDS: adult respiratory distress syndrome; CT: computed tomography.</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="table-head " align="" valign="top" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Respiratory distress \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">ARDS \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Definition \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Symptoms of respiratory distress with severe hypoxaemia secondary to interstitial lung involvement caused by increased alveolar permeability<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">2</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">The following must be met<a class="elsevierStyleCrossRef" href="#bib0280"><span class="elsevierStyleSup">22</span></a>:<br>Establishment of distress within the first week after occurrence of known lung damage<br>Bilateral opacities on chest radiography or CT, not justified entirely by pleural effusion, atelectasis or pulmonary nodules<br>Respiratory failure is not fully explained by heart failure or fluid overload<a class="elsevierStyleCrossRef" href="#tblfn0010"><span class="elsevierStyleSup">b</span></a><br>Deterioration in oxygenation<a class="elsevierStyleCrossRef" href="#tblfn0015"><span class="elsevierStyleSup">c</span></a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Causes \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Hyperventilation secondary to severe metabolic acidosis caused by hyperlactataemia<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a><br>Concomitant pneumonia<br>Fluid overload<br>Severe anaemia<br>ARDS \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Sepsis<br>Aspiration pneumonia<br>Bacterial/viral infection<br>Idiopathic<a class="elsevierStyleCrossRefs" href="#bib0180"><span class="elsevierStyleSup">2,10</span></a> \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1136991.png" ] ] ] "notaPie" => array:3 [ 0 => array:3 [ "identificador" => "tblfn0005" "etiqueta" => "a" "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Caused by the production of lactic acid by the parasite, tissue hypoperfusion or renal failure acidosis. It is the most common type of distress in African children, and is also common in adults.<a class="elsevierStyleCrossRef" href="#bib0285"><span class="elsevierStyleSup">23</span></a> It seems that hyperventilation contributes to pulmonary oedema, although both may occur simultaneously.<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">6</span></a></p>" ] 1 => array:3 [ "identificador" => "tblfn0010" "etiqueta" => "b" "nota" => "<p class="elsevierStyleNotepara" id="npar0010">In the absence of risk factors for ARDS, an objective assessment is required to exclude hydrostatic pulmonary oedema (e.g. by echocardiography).</p>" ] 2 => array:3 [ "identificador" => "tblfn0015" "etiqueta" => "c" "nota" => "<p class="elsevierStyleNotepara" id="npar0015">Defined by the relationship between the arterial partial pressure of oxygen (PaO<span class="elsevierStyleInf">2</span>)/fraction of inspired oxygen (FiO<span class="elsevierStyleInf">2</span>) or by the ratio between the peripheral oxygen saturation (SpO<span class="elsevierStyleInf">2</span>, measured by pulse oximetry) and FiO<span class="elsevierStyleInf">2</span> (SpO<span class="elsevierStyleInf">2</span>/FiO<span class="elsevierStyleInf">2</span>). The degree of hypoxaemia defines the severity of ARDS.</p>" ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Characteristics of respiratory distress and adult respiratory distress syndrome in malaria.</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 [ "leyenda" => "<p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">DIC: disseminated intravascular coagulation; ARDS: adult respiratory distress syndrome.</p><p id="spar0045" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleItalic">Source</span>: Maguire et al.,<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">15</span></a> Anstey et al.,<a class="elsevierStyleCrossRef" href="#bib0260"><span class="elsevierStyleSup">18</span></a> Ranieri et al.,<a class="elsevierStyleCrossRef" href="#bib0285"><span class="elsevierStyleSup">23</span></a> Sherman,<a class="elsevierStyleCrossRef" href="#bib0290"><span class="elsevierStyleSup">24</span></a> Tan et al.,<a class="elsevierStyleCrossRef" href="#bib0295"><span class="elsevierStyleSup">25</span></a> and Phu et al.<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">26</span></a></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="table-head " align="" valign="top" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black"><span class="elsevierStyleItalic">P. falciparum</span>, <span class="elsevierStyleItalic">P. knowlesi</span> \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black"><span class="elsevierStyleItalic">P. vivax</span>, <span class="elsevierStyleItalic">P. ovale</span> \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Onset of ARDS \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Onset of symptoms \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2–3 days from antimalarial treatment initiation (up to 14 days) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Parasitaemia \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">High \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Negative or declining \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Associated complications \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Cerebral malaria, renal failure, acidosis, hypoglycaemia, DIC \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Usually the only complication. Acute renal failure can be associated \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1136990.png" ] ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Clinical differences of adult respiratory distress syndrome based on the <span class="elsevierStyleItalic">Plasmodium</span> causal species.</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:34 [ 0 => array:3 [ "identificador" => "bib0175" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Achieving the malaria MDG target: reversing the incidence of malaria 2000–2015" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "World Health Organization" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Libro" => array:3 [ "fecha" => "2015" "editorial" => "WHO" "editorialLocalizacion" => "Geneva" ] ] ] ] ] ] 1 => array:3 [ "identificador" => "bib0180" "etiqueta" => "2" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Respiratory manifestations of malaria" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "W.R. 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