Corresponding author at: Pulmonology Department, Centro Hospitalar Vila Nova de Gaia e Espinho, Rua Conceição Fernandes, 4434-502 Vila Nova de Gaia, Portugal.
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Santos" "autores" => array:6 [ 0 => array:2 [ "nombre" => "Maria Inês" "apellidos" => "Matias" ] 1 => array:2 [ "nombre" => "Daniela Soares" "apellidos" => "Santos" ] 2 => array:2 [ "nombre" => "Maria Teresa" "apellidos" => "Dias" ] 3 => array:2 [ "nombre" => "Patrícia" "apellidos" => "Carvalho" ] 4 => array:2 [ "nombre" => "Arsénio" "apellidos" => "Santos" ] 5 => array:2 [ "nombre" => "Rui M." "apellidos" => "Santos" ] ] ] ] ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2531043719301746?idApp=UINPBA00004E" "url" => "/25310437/0000002600000003/v1_202005111106/S2531043719301746/v1_202005111106/en/main.assets" ] "en" => array:16 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Letter to the Editor</span>" "titulo" => "rs1573858 GATA-2 homozygote variant associated with pulmonary alveolar proteinosis, cytopenia and neurologic dysfunction" "tieneTextoCompleto" => true "saludo" => "Dear editor," "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "178" "paginaFinal" => "180" ] ] "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "N. China, C. Gurioli, S. Maitan, V. Poletti" "autores" => array:4 [ 0 => array:4 [ "nombre" => "N." "apellidos" => "China" "email" => array:1 [ 0 => "nunofilipechina@msn.com" ] "referencia" => array:3 [ 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" => "*" "identificador" => "cor0005" ] ] ] 1 => array:3 [ "nombre" => "C." "apellidos" => "Gurioli" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0010" ] ] ] 2 => array:3 [ "nombre" => "S." "apellidos" => "Maitan" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">c</span>" "identificador" => "aff0015" ] ] ] 3 => array:3 [ "nombre" => "V." "apellidos" => "Poletti" "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0010" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">d</span>" "identificador" => "aff0020" ] ] ] ] "afiliaciones" => array:4 [ 0 => array:3 [ "entidad" => "Pulmonology Department, Centro Hospitalar Vila Nova de Gaia e Espinho, Vila Nova de Gaia, Portugal" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Department of Diseases of the Thorax, Ospedale G.B. Morgagni, Forlì, Italy" "etiqueta" => "b" "identificador" => "aff0010" ] 2 => array:3 [ "entidad" => "Department of Anesthesiology, Ospedale G.B. Morgagni, Forlì, Italy" "etiqueta" => "c" "identificador" => "aff0015" ] 3 => array:3 [ "entidad" => "Department of Respiratory Diseases & Allergy, Aarhus University Hospital, Aarhus Denmark" "etiqueta" => "d" "identificador" => "aff0020" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author at: Pulmonology Department, Centro Hospitalar Vila Nova de Gaia e Espinho, Rua Conceição Fernandes, 4434-502 Vila Nova de Gaia, Portugal." ] ] ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:8 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 281 "Ancho" => 1250 "Tamanyo" => 84292 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0005" "detalle" => "Figure " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">“Pulmonary alveolar proteinosis – imaging. Chest CT showing diffuse ground-glass areas with juxtaposition of healthy zones and thickening of the interlobular septa — <span class="elsevierStyleItalic">crazy-paving”.</span></p>" ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall">Pulmonary alveolar proteinosis (PAP) is a syndrome characterized by the accumulation of alveolar surfactant. Although auto-immune PAP is responsible for 90% of all cases, association with genetic abnormalities has also been established.<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1,2</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">The authors present the case of a 43 years old non-smoker female. She has a previous medical history of idiopathic CD4 lymphocytopenia, idiopathic segmental dystonia, lymphedema and septicaemia due to parvovirus B19. Two years ago, she was treated for <span class="elsevierStyleItalic">Pneumocystis jiroveci</span> pneumonia with cotrimoxazol with clinical resolution.</p><p id="par0015" class="elsevierStylePara elsevierViewall">Ten months ago, she was admitted to Hospital for dyspnea with acute respiratory failure. She was assumed to have had acute cardiac failure with good response after diuretic treatment. After discharge, the echocardiogram was normal but in this context she performed a thoracic computed tomography scan which showed diffuse pulmonary ground-glass opacities and slight thickening of the interlobular septa — “<span class="elsevierStyleItalic">crazy-paving</span>” pattern (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>). At this time, she was referred to our Department of Thoracic Diseases due to these imaging findings and chronic respiratory insufficiency. She performed bronchoalveolar lavage that evidenced rare alveolar macrophages in an amorphous granular background with proteinaceous material; the cytopathological study was negative for malignant tumour cells and microbiological study showed no pathogenic microorganisms. Routine blood tests reported: hemoglobin 9.0 g/dL, platelets 59,000/µL, leukocytes 3100/µL, neutrophils 1181/µL, lymphocytes 1160/µL and monocytes 40/µL. Results were positive (1:320) for antinuclear antibodies (ANA), and negative for anti-neutrophil cytoplasmic antibodies (ANCA) and anti-extractable nuclear antigens (ENA) antibodies. Anti-granulocyte-macrophage colony-stimulating factor (anti-GM-CSF) antibodies were negative. A required genetic test for GATA-2 gene mutation identified a rs1573858 homozygote, benign variant. Although this mutation is considered not pathogenic, the whole clinical profile, except segmental dystonia, is typical of GATA-2 deficiency. Therefore, she was diagnosed with GATA-2 deficiency related PAP and whole lung lavage (WLL) was proposed. Right WLL was initially performed. A total of eight litres of warmed saline solution was instilled in the right lung and the fluid was then consecutively collected by gravity after opening an outflow tube. The procedure was aided by mechanical chest percussion. After 20 days, left WLL was performed with eight litres of saline solution (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>). There were no procedure complications and currently the patient does not require oxygen therapy.</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><elsevierMultimedia ident="fig0010"></elsevierMultimedia><p id="par0020" class="elsevierStylePara elsevierViewall">Macrophage homeostasis is highly relevant to lung hygiene. Conditions reducing either the number or functions of alveolar macrophages would be expected to reduce their capacity to clear surfactant from the lung surface, promoting secondary PAP.<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1,3</span></a></p><p id="par0025" class="elsevierStylePara elsevierViewall">GATA-2 belongs to a family of transcription factors that are critical regulators of gene expression in hematopoietic cells. Therefore, GATA-2 gene mutations may lead to haploinsufficiency associated with profound cytopenias. It remains unclear why but dendritic cells, monocytes, B and NK lymphoid cells are the ones mainly affected.<a class="elsevierStyleCrossRefs" href="#bib0015"><span class="elsevierStyleSup">3,4</span></a> Given this involvement, an association between GATA-2 insufficiency and PAP is to be expected. Given the usual abundance of alveolar macrophages in bronchoalveolar lavage fluid of these patients, PAP in GATA-2 deficiency must reflect more an alveolar macrophage dysfunction than a quantitative deficit, presumably by direct effects on alveolar macrophage phagocytosis.<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> GATA-2 also interacts with different signaling cascades through modulating the expression of key receptors or transducing proteins, such as M-CSF receptor or phospholipase C.<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a><span class="elsevierStyleItalic">Collin et al.</span><a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> reported the presence of 18% of PAP and 50% of abnormal pulmonary function cases in GATA-2 deficiency while <span class="elsevierStyleItalic">Vinh</span> et al.<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> found it in 33% of patients. As expected, our patient had no detectable anti-GM-CSF antibodies. In our case, the mutation identified is considered a benign variant. However the clinical profile (except the segmental dystonia) is typically observed in GATA-2 deficiency and therefore another unidentified genetic hit may be hypothesized as a promoter factor.</p><p id="par0030" class="elsevierStylePara elsevierViewall">The literature has highlighted the association between PAP and secondary opportunistic infections. However some studies have suggested that these microorganisms may even contribute to a secondary PAP.<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2,6</span></a> In our report, the patient presented a previous <span class="elsevierStyleItalic">Pneumocystis jiroveci</span> pneumonia. The authors question whether the potential role of <span class="elsevierStyleItalic">Pneumocystis jiroveci</span> is another contributing factor.</p><p id="par0035" class="elsevierStylePara elsevierViewall">In recent years, some clinical syndromes have been associated with GATA-2 deficiency. <span class="elsevierStyleItalic">Vinh</span> et al. described in 2010 the <span class="elsevierStyleItalic">Dendritic cell, Monocyte, B and NK Lymphoid Human Deficiency</span> (DCML) <span class="elsevierStyleItalic">Syndrome</span>. This syndrome results from a progressive absence of multi-lymphoid or lymphoid-primed multipotent progenitors and a severe depletion of CD38+ granulocytic monocytic progenitors.<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> In our report, the patient has a previous medical history of idiopathic CD4 lymphocytopenia. Considering these data, GATA-2 deficiency proved to be the explanation for the patient idiopathic CD4 lymphocytopenia. At the time of PAP diagnosis the patient also presented with a severe monocytopenia and a mild neutropenia. These findings are suggestive of DCML syndrome. However, a more detailed haematological study must be carried out to confirm this hypothesis. <span class="elsevierStyleItalic">Ferreira et al.</span> also described a patient with PAP that fulfilled the diagnostic criteria for DCML syndrome but until that date they had not confirmed the GATA-2 mutation.<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a></p><p id="par0040" class="elsevierStylePara elsevierViewall">WLL is the current standard of care in auto-immune PAP.<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> However, some secondary PAP cases have poor response to WLL and no reported series have specifically evaluated GATA-2 deficiency related PAP. In our report the patient presented an optimal clinical response. It will be important to note the clinical evolution in the coming months.</p><p id="par0045" class="elsevierStylePara elsevierViewall">To sum up, our report shows a very rare cause of PAP suggesting that a benign variant of GATA-2 mutation may contribute to the onset of a complex syndrome. This emphasizes the need to search for secondary causes as well as the current available treatments.</p><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0005">Author contributions</span><p id="par0050" class="elsevierStylePara elsevierViewall">Venerino Poletti and Stefano Maitan conceived the idea and made the diagnosis. Nuno China and Venerino Poletti collected the data and wrote the manuscript. Venerino Poletti and Carlo Gurioli were responsible for cytopathologic analysis. All the authors have read and approved the final version.</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Ethical disclosures</span><p id="par0055" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">Protection of human and animal subjects.</span> The authors declare that no experiments were performed on humans or animals for this study.</p><p id="par0060" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">Confidentiality of data.</span> The authors declare that they have followed the protocols of their work center on the publication of patient data.</p><p id="par0065" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">Right to privacy and informed consent.</span> The authors declare that no patient data appear in this article.</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Conflicts of interest</span><p id="par0070" class="elsevierStylePara elsevierViewall">The authors have no conflicts of interest to declare.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:4 [ 0 => array:2 [ "identificador" => "sec0005" "titulo" => "Author contributions" ] 1 => array:2 [ "identificador" => "sec0010" "titulo" => "Ethical disclosures" ] 2 => array:2 [ "identificador" => "sec0015" "titulo" => "Conflicts of interest" ] 3 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2019-06-23" "apendice" => array:1 [ 0 => array:1 [ "seccion" => array:1 [ 0 => array:4 [ "apendice" => "<p id="par0080" class="elsevierStylePara elsevierViewall">The following are Supplementary data to this article:<elsevierMultimedia ident="upi0005"></elsevierMultimedia></p>" "etiqueta" => "Appendix A" "titulo" => "Supplementary data" "identificador" => "sec0025" ] ] ] ] "multimedia" => array:3 [ 0 => array:8 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 281 "Ancho" => 1250 "Tamanyo" => 84292 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0005" "detalle" => "Figure " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">“Pulmonary alveolar proteinosis – imaging. 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Year/Month | Html | Total | |
---|---|---|---|
2024 November | 4 | 3 | 7 |
2024 October | 45 | 29 | 74 |
2024 September | 60 | 23 | 83 |
2024 August | 71 | 36 | 107 |
2024 July | 70 | 31 | 101 |
2024 June | 56 | 33 | 89 |
2024 May | 55 | 38 | 93 |
2024 April | 66 | 34 | 100 |
2024 March | 57 | 20 | 77 |
2024 February | 45 | 25 | 70 |
2024 January | 44 | 29 | 73 |
2023 December | 28 | 20 | 48 |
2023 November | 54 | 47 | 101 |
2023 October | 40 | 37 | 77 |
2023 September | 32 | 24 | 56 |
2023 August | 40 | 23 | 63 |
2023 July | 41 | 36 | 77 |
2023 June | 61 | 18 | 79 |
2023 May | 56 | 37 | 93 |
2023 April | 41 | 23 | 64 |
2023 March | 68 | 24 | 92 |
2023 February | 50 | 19 | 69 |
2023 January | 39 | 24 | 63 |
2022 December | 68 | 30 | 98 |
2022 November | 57 | 35 | 92 |
2022 October | 92 | 47 | 139 |
2022 September | 57 | 33 | 90 |
2022 August | 52 | 43 | 95 |
2022 July | 68 | 50 | 118 |
2022 June | 51 | 34 | 85 |
2022 May | 72 | 37 | 109 |
2022 April | 38 | 44 | 82 |
2022 March | 65 | 47 | 112 |
2022 February | 49 | 38 | 87 |
2022 January | 65 | 53 | 118 |
2021 December | 61 | 53 | 114 |
2021 November | 46 | 32 | 78 |
2021 October | 45 | 59 | 104 |
2021 September | 30 | 31 | 61 |
2021 August | 35 | 38 | 73 |
2021 July | 48 | 27 | 75 |
2021 June | 48 | 38 | 86 |
2021 May | 30 | 47 | 77 |
2021 April | 95 | 100 | 195 |
2021 March | 44 | 46 | 90 |
2021 February | 31 | 29 | 60 |
2021 January | 43 | 25 | 68 |
2020 December | 35 | 34 | 69 |
2020 November | 32 | 20 | 52 |
2020 October | 37 | 27 | 64 |
2020 September | 43 | 43 | 86 |
2020 August | 78 | 48 | 126 |
2020 July | 115 | 56 | 171 |
2020 June | 88 | 43 | 131 |
2020 May | 127 | 63 | 190 |
2020 April | 43 | 10 | 53 |
2020 March | 25 | 16 | 41 |
2020 February | 26 | 19 | 45 |
2020 January | 39 | 20 | 59 |
2019 December | 30 | 28 | 58 |
2019 November | 27 | 13 | 40 |
2019 October | 4 | 4 | 8 |