Macrophage activation syndrome induced by prolonged treatment with liposomal amphotericin B

Jung, Gerhard; Reverter, Enric; Fernández, Javier

doi:10.1016/j.medcle.2018.05.022

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The arrows indicate histiocytes with peripheral nuclei and an elongated and granular cytoplasm; (c and d) lower and higher increase in immunohistochemical staining of CD68, confirming the presence of abundant histiocytes." ] ] ] "textoCompleto" => "The macrophage activation syndrome (MAS) is a rare entity characterized by the uncontrolled proliferation and activation of macrophages that invade other tissues such as bone marrow, liver or spleen, and can cause a variety of non-specific symptoms such as fever, cytopenia and abnormal liver function tests.<a class="elsevierStyleCrossRef" href="#bib0030">1</a> Due to the non-specificity of these symptoms, the lack of well-defined diagnostic criteria and its low prevalence, it is probably an underdiagnosed entity, although potentially severe. More and more cases are recognized in the adult population secondary to a great variety of triggers. Nevertheless, drug-induced cases are rare.We report the case of a 53-year-old male patient, admitted to the ICU and recently recovered from a multiorgan failure, who developed atypical ulcers in both lower limbs 10 days after his admission to the ICU. Skin biopsies revealed an invasive fungal infection by Mucor. Treatment was started with liposomal amphotericin-B (LAmB), posaconazole and anidulafungin. Surgical debridement was performed 3 times, with negative control biopsies from the second intervention. Triple antifungal therapy was maintained for a total of 61 days. After confirming the resolution of the infection, an autologous skin graft was performed, with good progression.Thirty-five days after initiating triple antifungal therapy, the patient presented with high fever refractory to antipyretics. Laboratory tests showed a normal leukocyte blood count, eosinophilia (11.5%, 600/mcl) and an abnormal liver function test (AlkP: 654IU/l; GGT: 287IU/l; bilirubin 2.0mg/dl, with normal transaminases). Microbiological cultures (blood cultures, urine cultures, stool cultures, bronchoalveolar aspirates and catheters) were persistently negative. A chest-abdomen-pelvis CT scan showed moderate ascites and hepatosplenomegaly, which did not exist at the time of admission. Tumor and autoimmunity markers were also negative. Macrophages were detected in the ascitic fluid (84%/1400cel/ml), and a massive infiltration by macrophages was observed in the pathological anatomy of the liver biopsy (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>). PET-CT showed an intense increase in bone marrow metabolism. After considering all the above, MAS was suspected. Serum ferritin and triglyceride levels were high (2184ng/ml and 629mg/dl, respectively), as well as the ESR (140mm/h). Plasma fibrinogen levels were normal. With the clinical suspicion of MAS induced by the prolonged administration of LAmB (63 cumulative days of treatment) said drug was discontinued. Fever disappeared in 4 days and the ascites in 2 weeks, the liver enzymes normalized within a month and ferritin levels decreased significantly (996mg/ml). PET performed 7 weeks after LAmB was discontinued showed a normal bone marrow metabolism.<elsevierMultimedia ident="fig0005"></elsevierMultimedia>In conclusion, our patient fulfilled 4 of the 9 diagnostic criteria of the MAS, established by the “MAS study group”: fever, hyperferritinaemia, hypertriglyceridemia, abnormal liver function tests.<a class="elsevierStyleCrossRef" href="#bib0035">2</a> The presence of abundant macrophages in the liver biopsy was highly suggestive of this diagnosis. All possible secondary causes described in the literature were ruled out, these included viral infections (Epstein–Barr virus, cytomegalovirus, human herpesvirus 6, HIV-1, H1N1, hepatitis A, B virus and C), bacterial infections (Staphylococcus, Salmonella, Legionella, Mycoplasma), neoplasms and autoimmune diseases.<a class="elsevierStyleCrossRef" href="#bib0035">2</a> The <a id="intr0010" class="elsevierStyleInterRef" href="http://www.pubmed.com/">www.pubmed.com</a> database was used for the search of cases secondary to drugs from the first description of the syndrome in 1985 to the present. Although no case of MAS induced by LAmB has been reported, it is well known that this antifungal has immunostimulant effects and is capable of increasing macrophage activity.<a class="elsevierStyleCrossRefs" href="#bib0040">3–5</a> The symptoms occurred 35 days after the start of LAmB and began to be resolved just days after its discontinuation. In addition, LAmB discontinuation was the only therapeutic measure established in the patient. The temporal relationship and the resolution of the symptoms following LAmB discontinuation supports our hypothesis that treatment with LAmB was the trigger in this case. According to the Naranjo algorithm calculation, the causal relationship between LAmB and MAS is probable (6 points). For all these reasons, MAS should be considered as a possible severe adverse reaction of prolonged treatment with LAmB. The case has been reported to the national pharmacovigilance system." "pdfFichero" => "main.pdf" "tienePdf" => true "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "Please cite this article as: Jung G, Reverter E, Fernández J. Síndrome de activación macrofágica inducido por administración prolongada de anfotericina-B liposomal. Med Clin (Barc). 2018;151:84–85." ] ] "multimedia" => array:1 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1874 "Ancho" => 2500 "Tamanyo" => 725123 ] ] "descripcion" => array:1 [ "en" => "(a and b) H&E staining of liver biopsy: (a) part of the cylinder that, at lower magnification, shows a normal architecture of the hepatic lobe; (b) higher magnification of “a”. The arrows indicate histiocytes with peripheral nuclei and an elongated and granular cytoplasm; (c and d) lower and higher increase in immunohistochemical staining of CD68, confirming the presence of abundant histiocytes." ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0015" "bibliografiaReferencia" => array:5 [ 0 => array:3 [ "identificador" => "bib0030" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Histiocytic disorders: recent insights into pathophysiology and practical guidelines" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "A. Filipovich" 1 => "K. McClain" 2 => "A. Grom" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.bbmt.2009.11.014" "Revista" => array:7 [ "tituloSerie" => "Biol Blood Marrow Transplant" "fecha" => "2010" "volumen" => "16" "numero" => "Suppl 1" "paginaInicial" => "S82" "paginaFinal" => "S89" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/19932759" "web" => "Medline" ] ] ] ] ] ] ] ] 1 => array:3 [ "identificador" => "bib0035" "etiqueta" => "2" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Clinical features and correct diagnosis of macrophage activation syndrome" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "R.Q. Cron" 1 => "S. Davi" 2 => "F. Minoia" 3 => "A. 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Kobayashi" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Antimicrob Agents Chemother" "fecha" => "1977" "volumen" => "11" "paginaInicial" => "154" "paginaFinal" => "160" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/836011" "web" => "Medline" ] ] ] ] ] ] ] ] 3 => array:3 [ "identificador" => "bib0045" "etiqueta" => "4" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Amphotericin B stimulates γδ T and NK cells, and enhances protection from Salmonella infection" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "J.F. Hedges" 1 => "A.M. Mitchell" 2 => "K. Jones" 3 => "E. Kimmel" 4 => "A.G. Ramstead" 5 => "D.T. Snyder" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1177/1753425914567692" "Revista" => array:6 [ "tituloSerie" => "Innate Immun" "fecha" => "2015" "volumen" => "21" "paginaInicial" => "598" "paginaFinal" => "608" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/25608515" "web" => "Medline" ] ] ] ] ] ] ] ] 4 => array:3 [ "identificador" => "bib0050" "etiqueta" => "5" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Therapeutic and immunomodulatory activities of short-course treatment of murine visceral leishmaniasis with KALSOME10, a new liposomal amphotericin B" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "M. Asad" 1 => "P. Bhattacharya" 2 => "A. Banerjee" 3 => "N. Ali" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1186/s12879-015-0928-6" "Revista" => array:5 [ "tituloSerie" => "BMC Infect Dis" "fecha" => "2015" "volumen" => "15" "paginaInicial" => "188" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/25884796" "web" => "Medline" ] ] ] ] ] ] ] ] ] ] ] ] ] "idiomaDefecto" => "en" "url" => "/23870206/0000015100000002/v1_201807220502/S2387020618302146/v1_201807220502/en/main.assets" "Apartado" => array:4 [ "identificador" => "43309" "tipo" => "SECCION" "en" => array:2 [ "titulo" => "Letters to the Editor" "idiomaDefecto" => true ] "idiomaDefecto" => "en" ] "PDF" => "https://static.elsevier.es/multimedia/23870206/0000015100000002/v1_201807220502/S2387020618302146/v1_201807220502/en/main.pdf?idApp=UINPBA00004N&text.app=https://www.elsevier.es/" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2387020618302146?idApp=UINPBA00004N"]

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Vol. 151. Issue 2.

Pages 84-85 (July 2018)

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