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    "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall">Pulmonary alveolar proteinosis &#40;PAP&#41; is a syndrome characterized by the accumulation of alveolar surfactant&#46; Although auto-immune PAP is responsible for 90&#37; of all cases&#44; association with genetic abnormalities has also been established&#46;<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1&#44;2</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">The authors present the case of a 43 years old non-smoker female&#46; She has a previous medical history of idiopathic CD4 lymphocytopenia&#44; idiopathic segmental dystonia&#44; lymphedema and septicaemia due to parvovirus B19&#46; Two years ago&#44; she was treated for <span class="elsevierStyleItalic">Pneumocystis jiroveci</span> pneumonia with cotrimoxazol with clinical resolution&#46;</p><p id="par0015" class="elsevierStylePara elsevierViewall">Ten months ago&#44; she was admitted to Hospital for dyspnea with acute respiratory failure&#46; She was assumed to have had acute cardiac failure with good response after diuretic treatment&#46; After discharge&#44; 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 &#8212; &#8220;<span class="elsevierStyleItalic">crazy-paving</span>&#8221; pattern &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46; At this time&#44; she was referred to our Department of Thoracic Diseases due to these imaging findings and chronic respiratory insufficiency&#46; She performed bronchoalveolar lavage that evidenced rare alveolar macrophages in an amorphous granular background with proteinaceous material&#59; the cytopathological study was negative for malignant tumour cells and microbiological study showed no pathogenic microorganisms&#46; Routine blood tests reported&#58; hemoglobin 9&#46;0&#8239;g&#47;dL&#44; platelets 59&#44;000&#47;&#181;L&#44; leukocytes 3100&#47;&#181;L&#44; neutrophils 1181&#47;&#181;L&#44; lymphocytes 1160&#47;&#181;L and monocytes 40&#47;&#181;L&#46; Results were positive &#40;1&#58;320&#41; for antinuclear antibodies &#40;ANA&#41;&#44; and negative for anti-neutrophil cytoplasmic antibodies &#40;ANCA&#41; and anti-extractable nuclear antigens &#40;ENA&#41; antibodies&#46; Anti-granulocyte-macrophage colony-stimulating factor &#40;anti-GM-CSF&#41; antibodies were negative&#46; A required genetic test for GATA-2 gene mutation identified a rs1573858 homozygote&#44; benign variant&#46; Although this mutation is considered not pathogenic&#44; the whole clinical profile&#44; except segmental dystonia&#44; is typical of GATA-2 deficiency&#46; Therefore&#44; she was diagnosed with GATA-2 deficiency related PAP and whole lung lavage &#40;WLL&#41; was proposed&#46; Right WLL was initially performed&#46; 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&#46; The procedure was aided by mechanical chest percussion&#46; After 20 days&#44; left WLL was performed with eight litres of saline solution &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>&#41;&#46; There were no procedure complications and currently the patient does not require oxygen therapy&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><elsevierMultimedia ident="fig0010"></elsevierMultimedia><p id="par0020" class="elsevierStylePara elsevierViewall">Macrophage homeostasis is highly relevant to lung hygiene&#46; Conditions reducing either the number or functions of alveolar macrophages would be expected to reduce their capacity to clear surfactant from the lung surface&#44; promoting secondary PAP&#46;<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1&#44;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&#46; Therefore&#44; GATA-2 gene mutations may lead to haploinsufficiency associated with profound cytopenias&#46; It remains unclear why but dendritic cells&#44; monocytes&#44; B and NK lymphoid cells are the ones mainly affected&#46;<a class="elsevierStyleCrossRefs" href="#bib0015"><span class="elsevierStyleSup">3&#44;4</span></a> Given this involvement&#44; an association between GATA-2 insufficiency and PAP is to be expected&#46; Given the usual abundance of alveolar macrophages in bronchoalveolar lavage fluid of these patients&#44; PAP in GATA-2 deficiency must reflect more an alveolar macrophage dysfunction than a quantitative deficit&#44; presumably by direct effects on alveolar macrophage phagocytosis&#46;<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&#44; such as M-CSF receptor or phospholipase C&#46;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a><span class="elsevierStyleItalic">Collin et al&#46;</span><a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> reported the presence of 18&#37; of PAP and 50&#37; of abnormal pulmonary function cases in GATA-2 deficiency while <span class="elsevierStyleItalic">Vinh</span> et al&#46;<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> found it in 33&#37; of patients&#46; As expected&#44; our patient had no detectable anti-GM-CSF antibodies&#46; In our case&#44; the mutation identified is considered a benign variant&#46; However the clinical profile &#40;except the segmental dystonia&#41; is typically observed in GATA-2 deficiency and therefore another unidentified genetic hit may be hypothesized as a promoter factor&#46;</p><p id="par0030" class="elsevierStylePara elsevierViewall">The literature has highlighted the association between PAP and secondary opportunistic infections&#46; However some studies have suggested that these microorganisms may even contribute to a secondary PAP&#46;<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2&#44;6</span></a> In our report&#44; the patient presented a previous <span class="elsevierStyleItalic">Pneumocystis jiroveci</span> pneumonia&#46; The authors question whether the potential role of <span class="elsevierStyleItalic">Pneumocystis jiroveci</span> is another contributing factor&#46;</p><p id="par0035" class="elsevierStylePara elsevierViewall">In recent years&#44; some clinical syndromes have been associated with GATA-2 deficiency&#46; <span class="elsevierStyleItalic">Vinh</span> et al&#46; described in 2010 the <span class="elsevierStyleItalic">Dendritic cell&#44; Monocyte&#44; B and NK Lymphoid Human Deficiency</span> &#40;DCML&#41; <span class="elsevierStyleItalic">Syndrome</span>&#46; This syndrome results from a progressive absence of multi-lymphoid or lymphoid-primed multipotent progenitors and a severe depletion of CD38&#43; granulocytic monocytic progenitors&#46;<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> In our report&#44; the patient has a previous medical history of idiopathic CD4 lymphocytopenia&#46; Considering these data&#44; GATA-2 deficiency proved to be the explanation for the patient idiopathic CD4 lymphocytopenia&#46; At the time of PAP diagnosis the patient also presented with a severe monocytopenia and a mild neutropenia&#46; These findings are suggestive of DCML syndrome&#46; However&#44; a more detailed haematological study must be carried out to confirm this hypothesis&#46; <span class="elsevierStyleItalic">Ferreira et al&#46;</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&#46;<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&#46;<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> However&#44; some secondary PAP cases have poor response to WLL and no reported series have specifically evaluated GATA-2 deficiency related PAP&#46; In our report the patient presented an optimal clinical response&#46; It will be important to note the clinical evolution in the coming months&#46;</p><p id="par0045" class="elsevierStylePara elsevierViewall">To sum up&#44; 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&#46; This emphasizes the need to search for secondary causes as well as the current available treatments&#46;</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&#46; Nuno China and Venerino Poletti collected the data and wrote the manuscript&#46; Venerino Poletti and Carlo Gurioli were responsible for cytopathologic analysis&#46; All the authors have read and approved the final version&#46;</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&#46;</span> The authors declare that no experiments were performed on humans or animals for this study&#46;</p><p id="par0060" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">Confidentiality of data&#46;</span> The authors declare that they have followed the protocols of their work center on the publication of patient data&#46;</p><p id="par0065" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">Right to privacy and informed consent&#46;</span> The authors declare that no patient data appear in this article&#46;</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&#46;</p></span></span>"
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Letter to the Editor
rs1573858 GATA-2 homozygote variant associated with pulmonary alveolar proteinosis, cytopenia and neurologic dysfunction
N. Chinaa,b,
Corresponding author
nunofilipechina@msn.com

Corresponding author at: Pulmonology Department, Centro Hospitalar Vila Nova de Gaia e Espinho, Rua Conceição Fernandes, 4434-502 Vila Nova de Gaia, Portugal.
, C. Guriolib, S. Maitanc, V. Polettib,d
a Pulmonology Department, Centro Hospitalar Vila Nova de Gaia e Espinho, Vila Nova de Gaia, Portugal
b Department of Diseases of the Thorax, Ospedale G.B. Morgagni, Forlì, Italy
c Department of Anesthesiology, Ospedale G.B. Morgagni, Forlì, Italy
d Department of Respiratory Diseases & Allergy, Aarhus University Hospital, Aarhus Denmark
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she was admitted to Hospital for dyspnea with acute respiratory failure&#46; She was assumed to have had acute cardiac failure with good response after diuretic treatment&#46; After discharge&#44; 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 &#8212; &#8220;<span class="elsevierStyleItalic">crazy-paving</span>&#8221; pattern &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46; At this time&#44; she was referred to our Department of Thoracic Diseases due to these imaging findings and chronic respiratory insufficiency&#46; She performed bronchoalveolar lavage that evidenced rare alveolar macrophages in an amorphous granular background with proteinaceous material&#59; the cytopathological study was negative for malignant tumour cells and microbiological study showed no pathogenic microorganisms&#46; Routine blood tests reported&#58; hemoglobin 9&#46;0&#8239;g&#47;dL&#44; platelets 59&#44;000&#47;&#181;L&#44; leukocytes 3100&#47;&#181;L&#44; neutrophils 1181&#47;&#181;L&#44; lymphocytes 1160&#47;&#181;L and monocytes 40&#47;&#181;L&#46; Results were positive &#40;1&#58;320&#41; for antinuclear antibodies &#40;ANA&#41;&#44; and negative for anti-neutrophil cytoplasmic antibodies &#40;ANCA&#41; and anti-extractable nuclear antigens &#40;ENA&#41; antibodies&#46; Anti-granulocyte-macrophage colony-stimulating factor &#40;anti-GM-CSF&#41; antibodies were negative&#46; A required genetic test for GATA-2 gene mutation identified a rs1573858 homozygote&#44; benign variant&#46; Although this mutation is considered not pathogenic&#44; the whole clinical profile&#44; except segmental dystonia&#44; is typical of GATA-2 deficiency&#46; Therefore&#44; she was diagnosed with GATA-2 deficiency related PAP and whole lung lavage &#40;WLL&#41; was proposed&#46; Right WLL was initially performed&#46; 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&#46; The procedure was aided by mechanical chest percussion&#46; After 20 days&#44; left WLL was performed with eight litres of saline solution &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>&#41;&#46; There were no procedure complications and currently the patient does not require oxygen therapy&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><elsevierMultimedia ident="fig0010"></elsevierMultimedia><p id="par0020" class="elsevierStylePara elsevierViewall">Macrophage homeostasis is highly relevant to lung hygiene&#46; Conditions reducing either the number or functions of alveolar macrophages would be expected to reduce their capacity to clear surfactant from the lung surface&#44; promoting secondary PAP&#46;<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1&#44;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&#46; Therefore&#44; GATA-2 gene mutations may lead to haploinsufficiency associated with profound cytopenias&#46; It remains unclear why but dendritic cells&#44; monocytes&#44; B and NK lymphoid cells are the ones mainly affected&#46;<a class="elsevierStyleCrossRefs" href="#bib0015"><span class="elsevierStyleSup">3&#44;4</span></a> Given this involvement&#44; an association between GATA-2 insufficiency and PAP is to be expected&#46; Given the usual abundance of alveolar macrophages in bronchoalveolar lavage fluid of these patients&#44; PAP in GATA-2 deficiency must reflect more an alveolar macrophage dysfunction than a quantitative deficit&#44; presumably by direct effects on alveolar macrophage phagocytosis&#46;<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&#44; such as M-CSF receptor or phospholipase C&#46;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a><span class="elsevierStyleItalic">Collin et al&#46;</span><a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> reported the presence of 18&#37; of PAP and 50&#37; of abnormal pulmonary function cases in GATA-2 deficiency while <span class="elsevierStyleItalic">Vinh</span> et al&#46;<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> found it in 33&#37; of patients&#46; As expected&#44; our patient had no detectable anti-GM-CSF antibodies&#46; In our case&#44; the mutation identified is considered a benign variant&#46; However the clinical profile &#40;except the segmental dystonia&#41; is typically observed in GATA-2 deficiency and therefore another unidentified genetic hit may be hypothesized as a promoter factor&#46;</p><p id="par0030" class="elsevierStylePara elsevierViewall">The literature has highlighted the association between PAP and secondary opportunistic infections&#46; However some studies have suggested that these microorganisms may even contribute to a secondary PAP&#46;<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2&#44;6</span></a> In our report&#44; the patient presented a previous <span class="elsevierStyleItalic">Pneumocystis jiroveci</span> pneumonia&#46; The authors question whether the potential role of <span class="elsevierStyleItalic">Pneumocystis jiroveci</span> is another contributing factor&#46;</p><p id="par0035" class="elsevierStylePara elsevierViewall">In recent years&#44; some clinical syndromes have been associated with GATA-2 deficiency&#46; <span class="elsevierStyleItalic">Vinh</span> et al&#46; described in 2010 the <span class="elsevierStyleItalic">Dendritic cell&#44; Monocyte&#44; B and NK Lymphoid Human Deficiency</span> &#40;DCML&#41; <span class="elsevierStyleItalic">Syndrome</span>&#46; This syndrome results from a progressive absence of multi-lymphoid or lymphoid-primed multipotent progenitors and a severe depletion of CD38&#43; granulocytic monocytic progenitors&#46;<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> In our report&#44; the patient has a previous medical history of idiopathic CD4 lymphocytopenia&#46; Considering these data&#44; GATA-2 deficiency proved to be the explanation for the patient idiopathic CD4 lymphocytopenia&#46; At the time of PAP diagnosis the patient also presented with a severe monocytopenia and a mild neutropenia&#46; These findings are suggestive of DCML syndrome&#46; However&#44; a more detailed haematological study must be carried out to confirm this hypothesis&#46; <span class="elsevierStyleItalic">Ferreira et al&#46;</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&#46;<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&#46;<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> However&#44; some secondary PAP cases have poor response to WLL and no reported series have specifically evaluated GATA-2 deficiency related PAP&#46; In our report the patient presented an optimal clinical response&#46; It will be important to note the clinical evolution in the coming months&#46;</p><p id="par0045" class="elsevierStylePara elsevierViewall">To sum up&#44; 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&#46; This emphasizes the need to search for secondary causes as well as the current available treatments&#46;</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&#46; Nuno China and Venerino Poletti collected the data and wrote the manuscript&#46; Venerino Poletti and Carlo Gurioli were responsible for cytopathologic analysis&#46; All the authors have read and approved the final version&#46;</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&#46;</span> The authors declare that no experiments were performed on humans or animals for this study&#46;</p><p id="par0060" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">Confidentiality of data&#46;</span> The authors declare that they have followed the protocols of their work center on the publication of patient data&#46;</p><p id="par0065" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">Right to privacy and informed consent&#46;</span> The authors declare that no patient data appear in this article&#46;</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&#46;</p></span></span>"
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Pulmonology

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